The flavodoxin-like domain is an around 170-residue domain with a flavin mononucleotide (FMN)-binding site. It is involved in electron transfer
reactions [,
].Structure analyses of several flavodoxin-like domains have shown that it is a wound α-β-α fold with a central 5-stranded parallel hydrophobic β-sheet flanked on either side by amphipathic α-helices [
,
,
]. The FMN is positioned at the tip of the C-terminal side of the β-sheet []. The fold correlates with a highly conserved, repetitive sequence pattern in which hydrophobic residues cluster in β-strands and have a 3-4-residue periodicity in α-helices [].This domain is found in a number of proteins including flavodoxin and nitric-oxide synthase. Flavodoxins are electron-transfer proteins that function in various electron transport systems. They bind one FMN molecule, which serves as a redox-active prosthetic group [
] and are functionally interchangeable with ferredoxins. They have been isolated from prokaryotes, cyanobacteria, and some eukaryotic algae. Nitric oxide synthase () produces nitric oxide from L-arginine and NADPH. Nitric oxide acts as a messenger molecule in the body.
WrbA (tryptophan (W) repressor-binding protein) was discovered in Escherichia coli, where it was proposed to play a role in regulation of the tryptophan operon [
], which has been put in question since then []. Instead, WrbA has been shown to have FMN-dependent NAD(P)H:quinone oxidoreductase acivity [,
]. A role in quinone detoxification has been proposed, supported by evidence suggesting its involvement in oxidative defense and/or cell signaling [,
].This entry also includes QR2 from Triphysaria versicolor. QR2 acts as a NAD(P)H:quinone oxidoreductase reducing quinones by a two-electron transfer mechanism [
].
Squalene synthase
(farnesyl-diphosphate farnesyltransferase)(SQS) and phytoene synthase
(PSY) share a number of functional similarities. These similarities are also reflected at the level of their primary structure [
,
,
]. In particular three well conserved regions are shared by SQS and PSY; they could be involved in substrate binding and/or the catalytic mechanism. SQS catalyzes the conversion of two molecules of farnesyl diphosphate (FPP) into squalene. It is the first committed step in the cholesterol biosynthetic pathway. The reaction carried out by SQS is catalyzed in two separate steps: the first is a head-to-head condensation of the two molecules of FPP to form presqualene diphosphate; this intermediate is then rearranged in a NADP-dependent reduction, to form squalene:2 FPP ->presqualene diphosphate + NADP ->squalene SQS is found in eukaryotes. In yeast it is encoded by the ERG9 gene, in mammals by the FDFT1 gene. SQS seems to be membrane-bound.PSY catalyzes the conversion of two molecules of geranylgeranyl diphosphate (GGPP)into phytoene. It is the second step in the biosynthesis of carotenoids from isopentenyl diphosphate. The reaction carried out by PSY is catalyzed in two separate steps: the first is a head-to-head condensation of the two molecules of GGPP to form prephytoene diphosphate; this intermediate is then rearranged to form phytoene.2 GGPP ->prephytoene diphosphate ->phytoene
PSY is found in all organisms that synthesize carotenoids: plants and
photosynthetic bacteria as well as some non-photosynthetic bacteria and fungi. In bacteria PSY is encoded by the gene crtB. In plants PSY is localized in the chloroplast.Both SQS and PSY share a number of functional similarities which are also reflected at the level of their primary structure. In particular, three well conserved regions are shared by SQS and PSY, which could be involved in substrate binding and/or the catalytic mechanism. This entry contains the second and third conserved regions located in the central part of these enzymes.
SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [
,
]. They are found in a great variety of intracellular or membrane-associated proteins [,
,
] for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.The SH3 domain has a characteristic fold which consists of five or six β-strands arranged as two tightly packed anti-parallel β-sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [
].The crystal structure of the SH3 domain of the cytoskeletal protein spectrin, and the solution structures of SH3 domains of phospholipase C (PLC-y) and phosphatidylinositol 3-kinase p85 alpha-subunit, have been determined [
,
,
]. In spite of relatively limited sequence similarity, their overall structures are similar. The domains belong to the α+β structural class, with five to eight β-strands forming 2 tightly-packed, anti-parallel β-sheets arranged in a barrel-like structure, and intervening loops sometimes forming helices. Conserved aliphatic and aromatic residues form a hydrophobic core (A11, L23, A29, V34, W42, L52 and V59 in PLC-y []) and a hydrophobic pocket on the molecular surface (L12, F13, W53 and P55 in PLC-y). The conserved core is believed to stabilise the fold, while the pocket is thought to serve as a binding site for target proteins. Conserved carboxylic amino acids located in the loops, on the periphery of the pocket (D14 and E22), may be involved in protein-protein interactions via proline-rich regions. The N- and C-terminal are packed in close proximity, indicating that they are independent structural modules.
This domain corresponds to the C-terminal intermembrane space (IMS) region from Protein ACCUMULATION AND REPLICATION OF CHLOROPLASTS 6 (ARC6) and its paralogue PARC6 [
]. ARC6 and PARC6 are components of the plastid division machinery which are essential for the chloroplast replication process [,
], which implies the assembly and constriction of the tubulin-like FtsZ ring on the stromal surface of the inner envelope membrane (IEM) and the dynamin-like ARC5ring on the cytosolic surface of the outer envelope membrane (OEM). ARC6 is evolutionarily related to the cyanobacterial cell division protein Ftn2/ZipN [
], having similar structures. This domain from ARC6 and PARC6 interacts with PDV2 and PDV1 respectively. PDV proteins recruit dynamin-like ARC5 ring to the chloroplast surface and mediate its constriction. ARC6/PARC6 are key to connect and coordinate FtsZ and ARC5 rings during fission [,
].
The MCM2-7 complex consists of six closely related proteins that are highly conserved throughout the eukaryotic kingdom. In eukaryotes, Mcm4 is a component of the MCM2-7 complex (MCM complex), which consists of six sequence-related AAA + type ATPases/helicases that form a hetero-hexameric ring [
]. MCM2-7 complex is part of the pre-replication complex (pre-RC). In G1 phase, inactive MCM2-7 complex is loaded onto origins of DNA replication [,
,
]. During G1-S phase, MCM2-7 complex is activated to unwind the double stranded DNA and plays an important role in DNA replication forks elongation [].The components of the MCM2-7 complex are: .
DNA replication licensing factor MCM2, DNA replication licensing factor MCM3, DNA replication licensing factor MCM4, DNA replication licensing factor MCM5, DNA replication licensing factor MCM6, DNA replication licensing factor MCM7, Mcm4 is thought to play a pivotal role in ensuring DNA replication occurs
only once per cell cycle. Phosphorylation of Mcm4 dramatically reduces itsaffinity for chromatin - it has been proposed that this cell cycle-dependent
phosphorylation is the mechanism that inactivates the MCM complex from lateS phase through mitosis, thus preventing illegitimate DNA replication during that period of the cell cycle [
].
Proteins synthesised on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer [
]. While clathrin mediates endocytic protein transport, and transport from ER to Golgi, coatomers primarily mediate intra-Golgi transport, as well as the reverse Golgi to ER transport of dilysine-tagged proteins []. For example, the coatomer COP1 (coat protein complex 1) is responsible for reverse transport of recycled proteins from Golgi and pre-Golgi compartments back to the ER, while COPII buds vesicles from the ER to the Golgi []. Coatomers reversibly associate with Golgi (non-clathrin-coated) vesicles to mediate protein transport and for budding from Golgi membranes []. Activated small guanine triphosphatases (GTPases) attract coat proteins to specific membrane export sites, thereby linking coatomers to export cargos. As coat proteins polymerise, vesicles are formed and budded from membrane-bound organelles. Coatomer complexes also influence Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In mammals, coatomer complexes can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins. Coatomer complexes are hetero-oligomers composed of at least an alpha, beta, beta', gamma, delta, epsilon and zeta subunits. This group represents Coatomer subunit alpha. Structural studies show the homo-oligomerization of this protein plays a key role in the stability of the coat complex [
,
]. In humans, defects in its expression are related to primary immunodeficiencies that lead to immune dysregulation, arthritis and interstitial lung disease [
]. This protein has also been related to Alzheimer's disease [].
Proteins synthesised on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer [
]. While clathrin mediates endocytic protein transport, and transport from ER to Golgi, coatomers primarily mediate intra-Golgi transport, as well as the reverse Golgi to ER transport of dilysine-tagged proteins []. For example, the coatomer COP1 (coat protein complex 1) is responsible for reverse transport of recycled proteins from Golgi and pre-Golgi compartments back to the ER, while COPII buds vesicles from the ER to the Golgi []. Coatomers reversibly associate with Golgi (non-clathrin-coated) vesicles to mediate protein transport and for budding from Golgi membranes []. Activated small guanine triphosphatases (GTPases) attract coat proteins to specific membrane export sites, thereby linking coatomers to export cargos. As coat proteins polymerise, vesicles are formed and budded from membrane-bound organelles. Coatomer complexes also influence Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In mammals, coatomer complexes can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins. Coatomer complexes are hetero-oligomers composed of at least an alpha, beta, beta', gamma, delta, epsilon and zeta subunits. This entry represents the WD-associated region found in coatomer subunits alpha, beta and beta' subunits. The alpha-subunit (RET1P) of the coatomer complex in Saccharomyces cerevisiae (Baker's yeast), participates in membrane transport between the endoplasmic reticulum and Golgi apparatus. The protein contains six WD-40 repeat motifs in its N-terminal region [
].
Proteins synthesised on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer []. While clathrin mediates endocytic protein transport, and transport from ER to Golgi, coatomers primarily mediate intra-Golgi transport, as well as the reverse Golgi to ER transport of dilysine-tagged proteins []. For example, the coatomer COP1 (coat protein complex 1) is responsible for reverse transport of recycled proteins from Golgi and pre-Golgi compartments back to the ER, while COPII buds vesicles from the ER to the Golgi []. Coatomers reversibly associate with Golgi (non-clathrin-coated) vesicles to mediate protein transport and for budding from Golgi membranes []. Activated small guanine triphosphatases (GTPases) attract coat proteins to specific membrane export sites, thereby linking coatomers to export cargos. As coat proteins polymerise, vesicles are formed and budded from membrane-bound organelles. Coatomer complexes also influence Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In mammals, coatomer complexes can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins. Coatomer complexes are hetero-oligomers composed of at least an alpha, beta, beta', gamma, delta, epsilon and zeta subunits. This entry represents the C terminus (approximately 500 residues) of the eukaryotic coatomer alpha subunit [
,
]. This domain is found along with the domain.
FGGY carbohydrate kinases carry out ATP-dependent phosphorylation on one out of at least nine distinct sugar substrates [
]. These enzymes include L-ribulokinase () (gene araB); Erythriol kinase (
) (gene eryA); L-fucolokinase (
) (gene fucK); gluconokinase (
) (gene gntK); glycerol kinase (
) (gene glpK); xylulokinase (
) (gene xylB); L-xylulose kinase (
) (gene lyxK), D-ribulokinase (
) (gene rbtK); and rhamnulokinase (
) (gene rhaB). This family also contains a divergent subfamily functioning in quorum sensing, which phosphorylates AI-2, a bacterial signaling molecule derived from 4,5-dihydroxy-2,3-pentanedione (DPD) [
].All described members of this enzyme family are composed of two homologous actin-like ATPase domains. A catalytic cleft is formed by the interface between these two domains, where the sugar substrate and ATP co-substrate bind.This entry represents the C-terminal domain of these proteins. It adopts a ribonuclease H-like fold and is structurally related to the N-terminal domain [
,
].
FGGY carbohydrate kinases carry out ATP-dependent phosphorylation on one out of at least nine distinct sugar substrates [
]. These enzymes include L-ribulokinase () (gene araB); Erythriol kinase (
) (gene eryA); L-fucolokinase (
) (gene fucK); gluconokinase (
) (gene gntK); glycerol kinase (
) (gene glpK); xylulokinase (
) (gene xylB); L-xylulose kinase (
) (gene lyxK), D-ribulokinase (
) (gene rbtK); and rhamnulokinase (
) (gene rhaB). This family also contains a divergent subfamily functioning in quorum sensing, which phosphorylates AI-2, a bacterial signaling molecule derived from 4,5-dihydroxy-2,3-pentanedione (DPD) [
].This entry represents the N-terminal domain of these proteins. It adopts a ribonuclease H-like fold and is structurally related to the C-terminal domain [
,
].All described members of this enzyme family are composed of two homologous actin-like ATPase domains. A catalytic cleft is formed by the interface between these two domains, where the sugar substrate and ATP co-substrate bind.
This superfamily represents a domain found in a number of predicted metalloproteases. The crystal structure of the protein from the hyperthermophilic bacteria Aquifex aeolicus has been determined. The overall fold consists of one central α-helix surrounded by a four-stranded β-sheet and four other α-helices. Structure-based homology analysis reveals a good resemblance to metalloproteases such as collagenases and gelatinases. However, experimental tests for collagenase and gelatinase-type function show no detectable activity under standard assay conditions [
].
YbeY is a single strand-specific metallo-endoribonuclease involved in late-stage 70S ribosome quality control and in maturation of the 3' terminus of the 16S rRNA. It acts together with the RNase R to eliminate defective 70S ribosomes, but not properly matured 70S ribosomes or individual subunits, by a process mediated specifically by the 30S ribosomal subunit. It is involved in the processing of 16S, 23S and 5S rRNAs, with a particularly strong effect on maturation at both the 5'-and 3'-ends of 16S rRNA as well as maturation of the 5'-end of 23S and 5S rRNAs [
,
,
,
,
].The crystal structure of the protein from the hyperthermophilic bacteria Aquifex aeolicus has been determined. The overall fold consists of one central α-helix surrounded by a four-stranded β-sheet and four other α-helices. Structure-based homology analysis reveals a good resemblance to the metal-dependent proteinases such as collagenases and gelatinases. However, experimental tests for collagenase and gelatinase-type function show no detectable activity under standard assay conditions [
].
U1 small nuclear ribonucleoprotein of 70kDa N-terminal
Type:
Domain
Description:
This domain is about 90 amino acids in length and is found at the N terminus of U1 small nuclear ribonucleoprotein 70kDa (U1-70K), which is part of the U1 snRNP (snRNP) complex. U1 snRNP recognises the 5' splice site within precursor messenger RNAs and initiate the assembly of the spliceosome for intron excision.The N-terminal region of U1-70K extends over a distance of 180 A from its RNA binding domain, wraps around the core domain of U1 snRNP consisting of the seven Sm proteins and finally contacts U1-C, which is crucial for 5'-splice-site recognition [
].
Proteins identified by this conserved site are involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes in eukaryotes. Together with the EF-2-like GTPase RIA1, they may trigger the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export.
The proteins in this entry are highly conserved in species ranging from archaea to vertebrates and plants [
]. The family contains several Shwachman-Bodian-Diamond syndrome (SBDS, OMIM 260400) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition []. SBDS is required for the assembly of mature ribosomes and ribosome biogenesis [].Homologue of SBDS from budding yeast is known as Sdo1, which is a guanine nucleotide exchange factor (GEF) involved in ribosome maturation. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, allowing the assembly of mature ribosomes [
].
This entry represents the N-terminal domain of proteins that are highly conserved in species ranging from archaea to vertebrates and plants [
], including several Shwachman-Bodian-Diamond syndrome (SBDS, OMIM 260400) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition.Members of this entry play a role in RNA metabolism [
,
]. In yeast, SBDS orthologue SDO1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition [].The SBDS protein is composed of three domains. The N-terminal domain (FYSH, represented in this entry) is the most frequent target for disease mutations and contains a novel mixed α/β-fold, the central domain (
) consists of a three-helical bundle and the C-terminal domain (
) has a ferredoxin-like fold [
,
].
Ribosome maturation protein SDO1/SBDS, central domain
Type:
Domain
Description:
This entry represents the central domain of proteins that are highly conserved in species ranging from archaea to vertebrates and plants [
]. This entry contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans. Shwachman-Diamond syndrome (OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition.Members of this entry play a role in RNA metabolism [
,
]. In yeast, SBDS orthologue SDO1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition [].The SBDS protein is composed of three domains. The N-terminal (FYSH,
) domain is the most frequent target for disease mutations and contains a novel mixed α/β-fold, the central domain (represented in this entry) consists of a three-helical bundle and the C-terminal domain (
) has a ferredoxin-like fold [
,
].
The tetratrico peptide repeat region (TPR) is a structural motif present in a wide range of proteins [
,
,
]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel α-helices [
]. The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is ~24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B. This entry represents SHNi-TPR (Sim3-Hif1-NASP interrupted TPR), a sequence that is an interrupted form of TPR repeat [
].
This entry represents a transmembrane beta (8,10)-barrel found in outer membrane proteins such as OmpA, OmpX and NspA, and in the outer membrane enzyme PagP [
]. OmpA is multifunctional, being required for the action of colicins K and L, and for the stabilisation of mating aggregates in conjugation; it also serves as a receptor for a number of T-even like phages, and can act as a porin with low permeability that allows slow penetration of small solutes [
]. OmpX is a cation-selective channel that is regulated by osmolarity and by MarA expression []. NspA (Neisseria surface protein A) is an iron-activated membrane protein of unknown function []. The outer membrane enzyme PagP helps pathogenic bacteria to evade the host immune response catalysing palmitate transfer from a phospholipid to a glucosamine unit of lipid A [,
].
Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product.PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane [
,
,
]. Within the core of the complex, the chlorophyll and beta-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection []. In PSII, the oxygen-evolving complex (OEC) is responsible for catalysing the splitting of water to O(2) and 4H+. The OEC is composed of a cluster of manganese, calcium and chloride ions bound to extrinsic proteins. In cyanobacteria there are five extrinsic proteins in OEC (PsbO, PsbP-like, PsbQ-like, PsbU and PsbV), while in plants there are only three (PsbO, PsbP and PsbQ), PsbU and PsbV having been lost during the evolution of green plants [
].This family represents the PSII OEC protein PsbO, which appears to be the most important extrinsic protein for oxygen evolution. PsbO lies closest to the Mn cluster where water oxidation occurs, and has a stabilising effect on the Mn cluster. As a result, PsbO is often referred to as the Mn-stabilising protein (MSP), although none of its amino acids are likely ligands for Mn. Calcium ions were found to modify the conformation of PsbO in solution [
].
Cdc14 is a component of the septation initiation network (SIN) and is required for the localisation and activity of Sid1. Sid1 is a protein kinase that localises asymmetrically to one spindle pole body (SPB) in anaphase disappears prior to cell separation [
], [].
Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport [
]. Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors [,
].Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion [
,
]. The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase []. Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process []. The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins []. This entry represents a region covering the N-terminal β-propeller region of clathrin heavy chains that extends away from the hub of triskelia, and which is responsible for peptide binding [
], as well as the core motif for the α-helical zigzag linker region connecting the conserved N-terminal β-propeller region to the C-terminal α-α-superhelical region in clathrin heavy chains [].
Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport [
]. Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors [,
].Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion [
,
]. The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase []. Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process []. The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins []. This entry represents the α-helical zigzag linker region connecting the conserved N-terminal β-propeller region to the C-terminal α-α-superhelical region in clathrin heavy chains [
].
This entry represents the propeller repeat found in clathrin heavy chains. The N terminus of the heavy chain is known as the globular domain, and is composed of seven repeats which form a beta propeller [
].Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport [
]. Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors [,
].Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion [,
]. The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase []. Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process []. The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins [].
This group represents a clathrin heavy chain.Clathrin is a triskelion-shaped cytoplasmic protein that polymerises into a polyhedral lattice on intracellular membranes to form protein-coated membrane vesicles. Lattice formation induces the sorting of membrane proteins during endocytosis and organelle biogenesis by interacting with membrane-associated adaptor molecules. Clathrin consists of three heavy chain subunits, which are the main structural component of the clathrin vesicle coat, and three light chain molecules that interact with the heavy chains to self-assemble into a three-legged
triskelion structure. Each leg consists of one heavy chain and one light chain. The clathrin heavy-chain contains a 145-residue repeat that is present in seven copies [,
].
Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport [
]. Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors [,
].Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion [,
]. The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase []. Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process []. The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins []. This entry represents the core motif for the α-helical zigzag linker region connecting the conserved N-terminal β-propeller region to the C-terminal α-α-superhelical region in clathrin heavy chains [
].
Gamma-glutamyl cyclotransferase (GGCT) catalyzes the formation of pyroglutamic acid (5-oxoproline) from dipeptides containing gamma-glutamyl, and is a dimeric protein. In Homo sapiens, the protein is encoded by the gene C7orf24 [
]. The enzyme participates in the gamma-glutamyl cycle, which plays a pre-eminent role in glutathione homoeostasis []. The synthesis and metabolism of glutathione (L-gamma-glutamyl-L-cysteinylglycine) ties the gamma-glutamyl cycle to numerous cellular processes; glutathione acts as a ubiquitous reducing agent in reductive mechanisms involved in protein and DNA synthesis, transport processes, enzyme activity, and metabolism.AIG2 (avrRpt2-induced gene) is an Arabidopsis protein that exhibits RPS2- and avrRpt2-dependent induction early after infection with Pseudomonas syringae pv maculicola strain ES4326 carrying avrRpt2 [
,
]. avrRpt2 is an avirulence gene that can convert virulent strains of P. syringae to avirulence on Arabidopsis thaliana, soybean, and bean. This GGCT-like domain is also found in bacterial tellurite-resistance proteins (TrgB) [], butirosin biosynthesis protein BtrG [], and in proteins described as ChaC, involved in a novel pathway for glutathione degradation [].
This entry represents a domain found in a group of gamma-glutamyl cyclotransferases (GGCTs), including AIG2 from Arabidopsis. GGCT is a ubiquitous enzyme found in bacteria, plants, and metazoans from Dictyostelium through to humans. It converts gamma-glutamylamines to free amines and 5-oxoproline [
,
,
].AIG2 is an Arabidopsis protein that exhibit RPS2- and avrRpt2-dependent induction early after infection with Pseudomonas syringae pv maculicola strain ES4326 carrying avrRpt2 [
]. Its structure consists of a five-stranded β-barrel surrounded by two α-helices and a small β-sheet. A long flexible α-helix protrudes from the structure at the C-terminal end. Conserved residues in a hydrophilic cavity, which are able to bind small ligands, may act as an active site in AIG2-like proteins [].
The cysteine-rich secretory proteins (Crisp) are predominantly found in the mammalian male reproductive tract as well as in the venom of reptiles. This family includes mammalian testis-specific protein (Tpx-1), also known as cysteine-rich secretory protein 2 (CRISP2) [
]; venom allergen 5 from vespid wasps and venom allergen 3 from fire ants, which are potent allergens that mediate allergic reactions to stings insects of the Hymenoptera family []; scoloptoxins from Scolopendra dehaani (Thai centipede) []; plant pathogenesis proteins of the PR-1 family [], which are synthesised during pathogen infection or other stress-related responses; allurin, a sperm chemoattractant [], serotriflin [], etc.The precise function of some of these proteins is still unclear. Tpx-1 or CRISP2 may regulate some ion channels' activity and thereby regulate calcium fluxes during sperm capacitation [
].This entry also includes several Tabinhibitin proteins and allergen Tab y 5.0101 from horsefly salivary glands [
,
] and antigen 5 like allergen Cul n 1 from biting midge salivary glands [].
The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily proteins are found in a wide range of organisms, including prokaryotes [
] and non-vertebrate eukaryotes [], The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences []. The Ca2-chelating function [] would fit with the various signalling processes (e.g. the CRISP proteins) that members of this family are involved in, and also the sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how blocks the Ca2 transporting ryanodine receptors.
This entry represents the CAP domain common to all members of the CAP superfamily. The CAP domain forms a unique 3 layer α-β-α fold with some, though not all, of the structural elements found in proteases [
].
Proteins containing this domain include protein DA1 and its homologues.
In Arabidopsis thaliana, DA1 is a ubiquitin-activated endopeptidase that limits final seed and organ size by restricting the period of cell proliferation [
]. DA1 is activated by the RING E3 ligases Big Brother and DA2, both of which are then inactivated by cleavage by the active peptidase. DA1 also cleaves and inactivates deubiquitinase UBP15 and transcription factors TCP15 and TCP22, all of which promote cell proliferation. Presence of an HEXXH motif, which when mutated leads to inactivity, suggests that DA1 is a metalloendopeptidase [].
Glycosylphosphatidylinositol (GPI) represents an important anchoring molecule for cell surface proteins. The first step in its synthesis is the transfer of N-acetylglucosamine (GlcNAc) from UDP-N-acetylglucosamine to phosphatidylinositol (PI). This chemically simple step is genetically complex because three or four genes are required in both Saccharomyces cerevisiae (GPI1, GPI2 and GPI3) and mammals (GPI1, PIG A, PIG H and PIG C), respectively [
].This entry includes the mammalian Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PigQ), its homologue Phosphatidylinositol N-acetylglucosaminyltransferase subunit GPI1 (Gpi1) from yeast, and similar eukaryotic proteins. PigQ stabilises the complex of PIG-A, PIG-H, and PIG-C. It is important for the activity of this protein complex but not essential [
]. A similar function has been suggested for the yeast Gpi1 [].
DNA recombination/repair protein RecA, conserved site
Type:
Conserved_site
Description:
The recA gene product is a multifunctional enzyme that plays a role in homologous recombination, DNA repair and induction of the SOS response [
]. In homologous recombination, the protein functions as a DNA-dependent ATPase, promoting synapsis, heteroduplex formation and strand exchange between homologous DNAs []. RecA also acts as a protease cofactor that promotes autodigestion of the lexA product and phage repressors. The proteolytic inactivation of the lexA repressor by an activated form of recA may cause a derepression of the 20 or so genes involved in the SOS response, which regulates DNA repair, induced mutagenesis, delayed cell division and prophage induction in response to DNA damage []. RecA is a protein of about 350 amino acid residues. Its sequence is very well conserved [
,
,
] among eubacterial species. It is also found in the chloroplast of plants []. RecA-like proteins are found in archaea and diverse eukaryotic organisms, like fission yeast, mouse or human. In the filament visualised by X-ray crystallography, β-strand 3, the loop C-terminal to β-strand 2, and α-helix D of the core domain form one surface that packs against αa-helix A and β-strand 0 (the N-terminal domain) of an adjacent monomer during polymerisation []. The core ATP-binding site domain is well conserved, with 14 invariant residues. It contains the nucleotide binding loop between β-strand 1 and α-helix C. The Escherichia coli sequence GPESSGKT matches the consensus sequence of amino acids (G/A)XXXXGK(T/S) for the Walker A box (also referred to as the P-loop) found in a number of nucleoside triphosphate (NTP)-binding proteins. Another nucleotide binding motif, the Walker B box is found at β-strand 4 in the RecA structure. The Walker B box is characterised by four hydrophobic amino acids followed by an acidic residue (usually aspartate). Nucleotide specificity and additional ATP-binding interactions are contributed by the amino acid residues at β-strand 2 and the loop C-terminal to that strand, all of which are greater than 90% conserved among bacterial RecA proteins.This signature pattern is specific for the bacterial and chloroplastic RecA protein, and covers the most conserved region within these proteins, namely a nonapeptide located in the middle of the sequence and which is part of the monomer-monomer interface in a recA filament.
The recA gene product is a multifunctional enzyme that plays a role in homologous recombination, DNA repair and induction of the SOS response [
]. In homologous recombination, the protein functions as a DNA-dependent ATPase, promoting synapsis, heteroduplex formation and strand exchange between homologous DNAs []. RecA also acts as a protease cofactor that promotes autodigestion of the lexA product and phage repressors. The proteolytic inactivation of the lexA repressor by an activated form of recA may cause a derepression of the 20 or so genes involved in the SOS response, which regulates DNA repair, induced mutagenesis, delayed cell division and prophage induction in response to DNA damage []. RecA is a protein of about 350 amino-acid residues. Its sequence is very well conserved [
,
,
] among eubacterial species. It is also found in the chloroplast of plants []. RecA-like proteins are found in archaea and diverse eukaryotic organisms, like fission yeast, mouse or human. In the filamentvisualised by X-ray crystallography, β-strand 3, the loop C-terminal to β-strand 2, and α-helix D of the core domain form one surface that packs against α-helix A and β-strand 0 (the N-terminal domain) of an adjacent monomer during polymerisation []. The core ATP-binding site domain is well conserved, with 14 invariant residues. It contains the nucleotide binding loop between β-strand 1 and α-helix C. The Escherichia coli sequence GPESSGKT matches the consensus sequence of amino acids (G/A)XXXXGK(T/S) for the Walker A box (alsoreferred to as the P-loop) found in a number of nucleoside triphosphate (NTP)-binding proteins. Another
nucleotide binding motif, the Walker B box is found at β-strand 4 in the RecA structure. The Walker Bbox is characterised by four hydrophobic amino acids followed by an acidic residue (usually aspartate). Nucleotide specificity and additional ATP binding interactions are contributed by the amino acid residues at β-strand 2 and the loop C-terminal to that
strand, all of which are greater than 90% conserved among bacterial RecA proteins.
The HhH motif is a stretch of approximately 20 amino acids that is present in prokaryotic and
eukaryotic non-sequence-specific DNA binding proteins [,
,
]. The HhH motif is similar to, but distinct from, the HtH motif. Both of these
motifs have two helices connected by a short turn. In the HtH motif the secondhelix binds to DNA with the helix in the major groove. This allows the contact
between specific base and residues throughout the protein. In the HhH motifthe second helix does not protrude from the surface of the protein and
therefore cannot lie in the major groove of the DNA. Crystallographic studiessuggest that the interaction of the HhH domain with DNA is mediated by amino
acids located in the strongly conserved loop (L-P-G-V) and at the N-terminalend of the second helix [
]. This interaction could involve the formation ofhydrogen bonds between protein backbone nitrogens and DNA phosphate groups
[]. The structural difference between the HtH and HhH domains is reflected at the
functional level: whereas the HtH domain, found primarily in gene regulatoryproteins and binds DNA in a sequence specific manner, the HhH domain is rather
found in proteins involved in enzymatic activities and binds DNA with nosequence specificity [
].
Endonuclease III is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [
,
]. The structurally related DNA glycosylase MutYrecognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [
]. The 3-D structures of Escherichia coli endonuclease III [] and catalytic domain of MutY [] have been determined. Thestructures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key,
four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with theFe4S4 cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern
Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif isreferred to as a Fe4S4 cluster loop (FCL) [
]. Two DNA-binding motifs have been proposed, one at either end of theinterdomain groove: the helix-hairpin-helix (HhH) (see
) and FCL motifs (see
). The primary role of the iron-sulphur cluster appears to
involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop ofthe FCL motif [
,
].
Endonuclease III (
) is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [
,
]. The structurally related DNA glycosylase MutYrecognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [
]. The 3-D structures of Escherichia coli endonuclease III [] and catalytic domain of MutY [] have been determined. Thestructures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key,
four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with theFe4S4 cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern
Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif isreferred to as a Fe4S4 cluster loop (FCL) [
]. Two DNA-binding motifs have been proposed, one at either end of theinterdomain groove: the helix-hairpin-helix (HhH) and FCL motifs. The primary role of the iron-sulphur cluster appears to
involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop ofthe FCL motif [
,
]. The iron-sulphur cluster loop (FCL) is also found in DNA-(apurinic or apyrimidinic site) lyase, a subfamily of endonuclease III. The enzyme has both apurinic and apyrimidinic endonuclease activity and a DNA N-glycosylase activity. It cuts damaged DNA at cytosines, thymines and guanines, and acts on the damaged strand 5' of the damaged site. The enzyme binds a 4Fe-4S cluster which is not important for the catalytic activity, but is probably involved in the alignment of the enzyme along the DNA strand.
Endonuclease III is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [
,
]. The structurally related DNA glycosylase MutY recognises and excises the mutational intermediate 8-oxoguanine-adenine mispair []. The 3-D structures of Escherichia coli endonuclease III [] and catalytic domain of MutY [] have been determined. The structures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key, four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with the Fe4S4 cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif is referred to as a Fe4S4 cluster loop (FCL) []. Two DNA-binding motifs have been proposed, one at either end of the interdomain groove: the helix-hairpin-helix (HhH) region (see ) and FCL motif, described in this entry. The primary role of the iron-sulphur cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop of the FCL motif [
,
]. This signature pattern covers the four Cys residues that act as 4Fe-4S ligands.
This family consists of several eukaryotic Aph-1 proteins. Aph-1 is an essential subunit of the gamma-secretase complex, an endoprotease complex that catalyses the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signalling paradigm and as a key step in the pathogenesis of Alzheimer's disease [
]. It is thought that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. Aph-1 and Pen-2, two membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Co-expression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity [].
The sirtuin (also known as Sir2) family is broadly conserved from bacteria to human. Yeast Sir2 (silent mating-type information regulation 2),
the founding member, was first isolated as part of the SIR complex required for maintaining a modified chromatin structure at telomeres. Sir2 functionsin transcriptional silencing, cell cycle progression, and chromosome stability [
]. Although most sirtuins in eukaryotic cells are located in the nucleus, others are cytoplasmic or mitochondrial.This family is divided into five classes (I-IV and U) on the basis of a phylogenetic analysis of 60 sirtuins from a wide array of organisms [
]. Class I and class IV are further divided into three and two subgroups, respectively. The U-class sirtuins are found only in Gram-positive bacteria []. The S. cerevisiae genome encodes five sirtuins, Sir2 and four additional proteins termed 'homologues of sir two' (Hst1p-Hst4p) []. The human genome encodes seven sirtuins, with representatives from classes I-IV [,
].Sirtuins are responsible for a newly classified chemical reaction, NAD-dependent protein deacetylation. The final products of the reaction are the
deacetylated peptide and an acetyl ADP-ribose []. In nuclear sirtuins this deacetylation reaction is mainly directed against histones acetylated lysines [].Sirtuins typically consist of two optional and highly variable N- and C-terminal domain (50-300 aa) and a conserved catalytic core domain (~250 aa). Mutagenesis experiments suggest that the N- and C-terminal regions help direct catalytic core domain to different targets [
,
].The 3D-structure of an archaeal sirtuin in complex with NAD reveals that the protein consists of a large domain having a Rossmann fold and a small domain containing a three-stranded zinc ribbon motif. NAD is bound in a pocket between the two domains [
].
This entry represents the complete catalytic core domain of sirtuin proteins.The sirtuin (also known as Sir2) family is broadly conserved from bacteria to human. Yeast Sir2 (silent mating-type information regulation 2),
the founding member, was first isolated as part of the SIR complex required for maintaining a modified chromatin structure at telomeres. Sir2 functionsin transcriptional silencing, cell cycle progression, and chromosome stability [
]. Although most sirtuins in eukaryotic cells are located in the nucleus, others are cytoplasmic or mitochondrial.This family is divided into five classes (I-IV and U) on the basis of a phylogenetic analysis of 60 sirtuins from a wide array of organisms [
]. Class I and class IV are further divided into three and two subgroups, respectively. The U-class sirtuins are found only in Gram-positive bacteria []. The S. cerevisiae genome encodes five sirtuins, Sir2 and four additional proteins termed 'homologues of sir two' (Hst1p-Hst4p) []. The human genome encodes seven sirtuins, with representatives from classes I-IV [,
].Sirtuins are responsible for a newly classified chemical reaction, NAD-dependent protein deacetylation. The final products of the reaction are the
deacetylated peptide and an acetyl ADP-ribose []. In nuclear sirtuins this deacetylation reaction is mainly directed against histones acetylated lysines [].Sirtuins typically consist of two optional and highly variable N- and C-terminal domain (50-300 aa) and a conserved catalytic core domain (~250 aa). Mutagenesis experiments suggest that the N- and C-terminal regions help direct catalytic core domain to different targets [
,
].The 3D-structure of an archaeal sirtuin in complex with NAD reveals that the protein consists of a large domain having a Rossmann fold and a small domain containing a three-stranded zinc ribbon motif. NAD is bound in a pocket between the two domains [
].
Carbonic anhydrases (CA:
) are zinc metalloenzymes which catalyse the reversible hydration of carbon dioxide to bicarbonate [
,
]. CAs have essential roles in facilitating the transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the layers of the extracellular space; they are also involved in many other processes, from respiration and photosynthesis in eukaryotes to cyanate degradation in prokaryotes. There are five known evolutionarily distinct CA families (alpha, beta, gamma, delta and epsilon) that have no significant sequence identity and have structurally distinct overall folds. Some CAs are membrane-bound, while others act in the cytosol; there are several related proteins that lack enzymatic activity. The active site of alpha-CAs is well described, consisting of a zinc ion coordinated through 3 histidine residues and a water molecule/hydroxide ion that acts as a potent nucleophile. The enzyme employs a two-step mechanism: in the first step, there is a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide; in the second step, the active site is regenerated by the ionisation of the zinc-bound water molecule and the removal of a proton from the active site []. Beta- and gamma-CAs also employ a zinc hydroxide mechanism, although at least some beta-class enzymes do not have water directly coordinated to the metal ion. The alpha-CAs are found predominantly in animals but also in bacteria and green algae. There are at least 15 isoforms found in mammals, which can be subdivided into cytosolic CAs (CA-I, CA-II, CA-III, CA-VII and CA XIII), mitochondrial CAs (CA-VA and CA-VB), secreted CAs (CA-VI), membrane-associated (CA-IV, CA-IX, CA-XII and CA-XIV) and those without CA activity, the CA-related proteins (CA-RP VIII, X and XI).The beta-CAs are highly abundant in plants, diatoms, eubacteria and archaea [
,
]. The beta-CAs are far more diverse in sequence than other classes, and can be divided into different clades based on sequence identity, with the plant enzymes forming two clades representing dicotyledonous and monocotyledonous plants. Characterisation of these enzymes reveals sharp differences between the beta class, which forms dimers, tetramers, hexamers and octomers, and the alpha and gamma classes, which form strictly monomers and trimers. The gamma-CAs may be the most ancient form of carbonic anhydrases, having evolved long before the alpha class, to which it is more closely related than to the beta-class [
,
]. The reaction mechanism of the gamma-class is similar to that of the alpha-class, even though the overall folds are dissimilar and the active site residues differ. The delta-CAs are found in marine algae and dinoflagellates [
]. The epsilon-CAs are found in prokaryotes such as Thiobacillus neapolitanus (Halothiobacillus neapolitanus) in which it is a component of the carboxysome shell, where it could supply the active sites of RuBisCO in the carboxysome with the high concentrations of carbon dioxide necessary for optimal RuBisCO activity and efficient carbon fixation [
].This entry represents a conserved site based around one of the zinc-binding histidines in the alpha class of carbonic anhydrases.
The Rho termination factor disengages newly transcribed RNA from its DNA template at certain, specific transcripts. It is thought that two copies of Rho bind to RNA and that Rho functions as a hexamer of protomers [
]. This domain is found to the N terminus of the RNA binding domain ().
EMC3 is a subunit if the ER Membrane protein Complex (EMC), which is required for efficient folding of proteins in the endoplasmic reticulum (ER). Loss of the EMC leads to accumulation of misfolded membrane proteins [
].
This entry represents a group of eukaryotic and archaeal proteins. Eukaryotic members include EMC3, a subunit of the ER membrane protein complex (EMC) required for protein folding [
], and TMCO1, a ER calcium load-activated calcium channel []. Archaeal members may function as insertases of the archaeal plasma membrane [].
A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain
(ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain [,
].A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups [
]:The fimbrin family of monomeric actin cross-linking molecules containing two ABDsDimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABDProteins containing only a single amino terminal CH domain. Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability tobind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless
both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD throughinter-domain helix-helix interactions [
]. Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone []. In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices [
].Proteins containing a calponin domain include:Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells [
].Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins [
].The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins [
].Utrophin,a close homologue of dystrophin [
].Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains [
].Actin-binding domain of plectin, a large and widely expressed cytolinker protein [
].The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules [
].Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis [
].Transgelin, which suppresses androgen receptor transactivation [
].
This entry represents the N-terminal domain of DDA1 (DET1- and DDB1-associated protein 1) ubiquitin ligase, which binds strongly with Det1 (De-etiolated 1) and DDB1 (Damaged DNA binding protein 1 associated 1). Together DDA1, DDB1 and Det1 form the DDD core complex, which recruits a specific UBE2E enzyme to form specific DDD-E2 complexes [
]. Component of the DDD-E2 complexes which may provide a platform for interaction with cul4a and WD repeat proteins. These proteins may be involved in ubiquitination and subsequent proteasomal degradation of target proteins.
RNA (C5-cytosine) methyltransferases (RCMTs) catalyse the transfer of a methyl group to the 5th carbon of a cytosine base in RNA sequences to produce C5-methylcytosine. RCMTs use the cofactor S-adenosyl-L-methionine (SAM) as a methyl donor [
]. The catalytic mechanism of RCMTs involves an attack by the thiolate of a Cys residue on position 6 of the target cytosine base to form a covalent link, thereby activating C5 for methyl-group transfer. Following the addition of the methyl group, a second Cys residue acts as a general base in the beta-elimination of the proton from the methylated cytosine ring. The free enzyme is restored and the methylated product is released [].Numerous putative RCMTs have been identified in archaea, bacteria and eukaryota [
,
]; most are predicted to be nuclear or nucleolar proteins []. The Escherichia coli Ribosomal RNA Small-subunit Methyltransferase Beta (RSMB) FMU (FirMicUtes) represents the first protein identified and characterised as a cytosine-specific RNA methyltransferase. RSMB was reported to catalyse the formation of C5-methylcytosine at position 967 of 16S rRNA [,
].A classification of RCMTs has been proposed on the basis of sequence similarity [
]. According to this classification, RCMTs are divided into 8 distinct subfamilies []. Recently, a new RCMT subfamily, termed RCMT9, was identified []. Members of the RCMT contain a core domain, responsible for the cytosine-specific RNA methyltransferase activity. This 'catalytic' domain adopts the Rossman fold for the accommodation of the cofactor SAM []. The RCMT subfamilies are also distinguished by N-terminal and C-terminal extensions, variable both in size and sequence [].The prototypical member of the Nucleolar Protein 2 RCMT subfamily, the S.cerevisiae NOP2, is an essential nucleolar protein required for pre-rRNA processing and 60S ribosomal subunit assembly [
] that acts as a ribosomal RNA methyltransferase [,
]. Its human homologue, the proliferation-associated nucleolar antigen P120, is a promising tumour marker []. P120 has been demonstrated to be implicated in rRNA biogenesis [,
], and is also proposed to act as an rRNA methyltransferase [].
Bacterial Fmu (Sun)/eukaryotic nucleolar NOL1/Nop2p, conserved site
Type:
Conserved_site
Description:
This pattern is to a conserved central domain which contains some highly conserved regions, and which is found in archaeal, bacterial and eukaryotic proteins. In the archaea and bacteria, they are annotated as putative nucleolar protein, Sun (Fmu) family protein or tRNA/rRNA cytosine-C5-methylase. The majority have the S-adenosyl methionine (SAM) binding domain and are related to Escherichia coli Fmu (Sun) protein (16S rRNA m5C 967 methyltransferase) whose structure has been determined [
]. In the eukaryota, the majority are annotated as being 'hypothetical protein', nucleolar protein or the Nop2/Sun (Fmu) family. Unlike their bacterial homologues, few of the eukaryotic members in this family have a the SAM binding signature. Despite this, Saccharomyces cerevisiae (Baker's yeast) Nop2p is a probable RNA m5C methyltransferase [
]. It is essential for processing and maturation of 27S pre-rRNA and large ribosomal subunit biogenesis []; localized to the nucleolus and is essential for viability []. Reduced Nop2p expression limits yeast growth and decreases levels of mature 60S ribosomal subunits while altering rRNA processing []. There is substantial identity between Nop2p and Homo sapiens (Human) p120 (NOL1), which is also called the proliferation-associated nucleolar antigen [,
].
This domain is found in archaeal, bacterial and eukaryotic proteins. In the archaea and bacteria, they are primarily restricted to the euryarchaeota and proteobacteria respectively; where they are either described as either nucleolar protein or tRNA/rRNA cytosine-C5-methylase. They all have the S-adenosyl methionine (SAM) binding domain and are related to bacterial Fmu (16S rRNA m5C 967 methyltransferase) where the structure of the methyl transferase domain has been determined [
]. In the eukaryota, the majority are annotated as being 'nucleolar protein'. None of the eukaryotic members in this family have a the SAM binding signature. Despite this, the yeast Nop2p is a probable RNA m(5)C methyltransferase, essential for processing and maturation of 27S pre-rRNA and large ribosomal subunit biogenesis [
]; localised to the nucleolus and is essential for viability []. Reduced Nop2p expression limits yeast growth and decreases levels of mature 60S ribosomal subunits while altering rRNA processing []. There is substantial identity between Nop2p and human p120 (NOL1), which is also called the proliferation-associated nucleolar antigen [,
].
This entry represents cytochrome c oxidase assembly factors Sco1 and Sco2 (Synthesis of Cytochrome c Oxidase, factors 1 and 2), mitochondrial inner membrane-tethered metallochaperones that have regulatory roles in the maintenance of cellular copper homeostasis. These proteins are essential for the assembly of the catalytic core of cytochrome c oxidase (COX or complex IV), as well as other roles in copper homeostasis such as mitochondrial redox signalling [
]. Both Sco1 and Sco2 contain highly conserved CXXXC motifs thought to be required for copper binidng.COX is the terminal enzyme of the energy transducing respiratory chain in eukaryotes and certain prokaryotes. It catalyses the transfer of electrons from cytochrome c to molecular oxygen and pumps protons across the mitochondrial inner membrane to establish a proton gradient for ATP synthesis. It consists of 12-13 protein subunits, with 3 subunits (Cox1-Cox3) forming the enzyme core. COX uses haem and copper as cofactors: Cox1 contains a 1-copper centre (CuB) that interacts with the haem moiety and Cox2 contains a 2-copper centre (CuA). Sco1 and Sco2 act as copper chaperones, transporting copper to the CuA site in Cox2, and are thought to have cooperative functions in COX assembly [
,
]. In addition, human Sco2 is also the downstream mediator of the balance between the utilization of respiratory and glycolytic pathways [] and both Sco1 and Sco2 may have regulatory roles in regulating cellular copper levels (homeostasis) []. Sco2 may have a copper-level-detection signalling role, acting upstream and in conjunction with Sco1.Defects in Sco1 are a cause of cytochrome c oxidase deficiency (COX deficiency) (OMIM:220110), a clinically heterogeneous disorder with features ranging from isolated myopathy to severe multisystem disease, and onset from infancy to adulthood. Defects in Sco2 are the cause of fatal infantile cardioencephalomyopathy with cytochrome c oxidase deficiency (FIC) (OMIM:604377, OMIM:220110), which is characterised by hypertrophic cardiomyopathy, lactic acidosis, and gliosis.
The SCO (an acronym for Synthesis of Cytochrome c Oxidase) family is involved in biogenesis of respiratory and photosynthetic systems. Members of this family are required for the proper assembly of cytochrome c oxidase (COX). They contain a metal binding motif, typically CXXXC, which is located in a flexible loop. In yeast the SCO1 protein is specifically required for a post-translational step in the accumulation of subunits 1 and 2 of cytochrome c oxidase (COXI and COX-II) [
]. It is a mitochondrion-associated cytochrome c oxidase assembly factor, and a membrane-anchored protein possessing a soluble domain with a TRX fold []. The SCOP homologue in Bacillus subtilis is also required for the expression of cytochrome c oxidase []. It has been proposed that Sco1 specifically delivers copper to the CuA site, a dinuclear copper centre, of the COX II subunit. More recently, it has been argued that the redox sensitivity of the copper binding properties of Sco1 implies that it participates in signaling events rather than functioning as a chaperone that transfers copper to COX II [,
].The purple nonsulphur photosynthetic eubacterium Rhodobacter capsulatus is a versatile organism that can obtain cellular energy by several means, including the capture of light energy for photosynthesis as well as the use of light-independent respiration, in which molecular oxygen serves as a terminal electron acceptor. The SenC protein is required for optimal cytochrome c oxidase activity in aerobically grown R. capsulatus cells and is involved in the induction of structural polypeptides of the light-harvesting and reaction centre complexes [
].Mutations in human Sco1 and Sco2 cause fatal infantile hepatoencephalomyopathy and cardioencephalomyopathy, respectively. Both disorders are associated with severe COX deficiency in affected tissues [
].
ATP-binding cassette transporters (ABC) are multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. Members of ABC transporter subfamily A are full-length transporters [
], which consist of a single long polypeptide chain organised into two tandemly arranged halves. Each half contains a membrane-spanning domain (MSD) followed by a cytoplasmic nucleotide binding domain (NBD) []. Several members of this group have been shown to mediate the transport of a variety of physiologic lipid compounds, such as sterols, phospholipids and bile acids [,
].ABCA7 plays a role in clearance of apoptotic cells by affecting their phagocytosis [
]. In the human visual cycle, ABCA4 acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. ABCA4 may also play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery []. It has been suggested that ABCA9 plays a role in monocyte differentiation and lipid homeostasis [].
This domain can be found in bacterial, plant and other metazoa transmembrane proteins. Many of the members are multi-pass transmembrane proteins. This domain represents the N-terminal region which contains a conserved homology domain (CHD1) [
].
Villin is an F-actin bundling protein involved in the
maintenance of the microvilli of the absorptive epithelia. The villin-type "headpiece"domain is a modular motif found at the extreme C terminus of larger "core"domains in over 25 cytoskeletal proteins in plants and animals, often in assocation with the Gelsolin repeat. Although the headpiece is classified as an F-actin-binding domain, it has been shown that not all headpiece domains are intrinsically F-actin-binding motifs, surface charge distribution may be an important element for F-actin recognition [
]. An autonomously folding, 35 residue, thermostable subdomain (HP36) of the full-length 76 amino acid residue villin headpiece, is the smallest known example of a cooperatively folded domain of a naturally occurring protein. The structure of HP36, as determined by NMR spectroscopy, consists of three short helices surrounding a tightly packed hydrophobic core [].
Gelsolin is an actin-modulating protein that severs F-actin, caps the barbed ends of actin filaments preventing monomer exchange, and promotes the nucleation step of actin polymerisation [
,
]. It can be regulated by Ca2+ and phosphoinositides []. The interaction between gelsolin and tropomyosin modulates actin dynamics []. Gelsolin also plays a role in ciliogenesis []. The structure of gelsolin has been solved []. Villin is an actin-binding protein that is found in a variety of tissues. It is able to bind to the barbed end of actin filaments with high affinity and can sever filaments [
]. In addition, villin's activity is important for actin bundling in certain cell types []. It was first isolated as a major component of the core of intestinal microvilli [].Villin/gelsolin family includes other actin-binding proteins such as severin and supervillin [
]. Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. While the multiple repeats have yet to be related to any known function of the actin-severing proteins, the superfamily appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues [].
This presumed domain is found DTWD1/DTWD2 from humans and YfiP (also known as TapT) from Escherichia coli. The domain contains multiple conserved motifs including a DTXW motif that this domain has been named after. DTW domain containing protein may have a SAM-dependent acp transferase activity [
].
Cytoplasmic tRNA 2-thiolation protein 2 (also known as Ncs2/Tuc2 in budding yeasts) is responsible for 2-thiolation of mcm5S2U at tRNA wobble positions of tRNA(Lys), tRNA(Glu) and tRNA(Gln) [
,
]. Its fission yeast homologue, Ctu2 forms a complex with Ctu1 (Ncs6/Tuc1 homologue) and serves as a putative enzyme for the formation of 2-thiouridine [].
This family contains a domain common to the cobN protein and to magnesium protoporphyrin chelatase. CobN may play a role in cobalt insertion reactions and is implicated in the conversion of precorrin-2 to cobyrinic acid in cobalamin biosynthesis [
]. Magnesium protoporphyrin chelatase is involved inchlorophyll biosynthesis as the third subunit of light-independent protochlorophyllide reductase in bacteria and plants [
].
This functionally uncharacterised domain, found N-terminal to
, occurs in magnesium chelatase subunit H, which is involved in chlorophyll biosynthesis. It is found in bacteria, green plants and archaea. It is around 160 amino acids in length.
This entry represents the H subunit of the magnesium chelatase complex responsible for magnesium insertion into the protoporphyrin IX ring in the biosynthesis of both chlorophyll and bacteriochlorophyll. In chlorophyll-utilizing species, this gene is known as ChlH, while in bacteriochlorophyll-utilizing spoecies it is called BchH. Subunit H is the largest (~140kDa) of the three subunits (the others being BchD/ChlD and BchI/ChlI), and is known to bind protoporphyrin IX. Subunit H is homologous to the CobN subunit of cobaltochelatase and by anology with that enzyme, subunit H is believed to also bind the magnesium ion which is inserted into the ring. In conjunction with the hydrolysis of ATP by subunits I and D, a conformation change is believed to happen in subunit H causing the magnesium ion insertion into the distorted protoporphyrin ring [
].
The misato protein contains three distinct, conserved domains, segments I, II and III and is involved in the regulation of mitochondrial distribution and morphology [
]. This entry represents misato segment II.Segments I and III are common to tubulins (
), but segment II aligns with myosin heavy chain sequences from Drosophila melanogaster (Fruit fly,
), rabbit (
), and human.
Segment II of misato is a major contributor to its greater length compared with the various tubulins. The most significant sequence similarities to this 54-amino acid region are from a motif found in the heavy chains of myosins from different organisms. A comparison of segment II with the vertebrate myosin heavy chains reveals that it shares homology with a myosin peptide in the hinge region linking the S2 and LMM domains. Segment II also contains heptad repeats which are characteristic of the myosin tail α-helical coiled-coils [
].
This entry consists of proteins from eukaryotes and prokarytotes. It includes Escherichia coli autoinducer-2 (AI-2) transport protein TqsA (YdgG), which controls the transport of the quorum-sensing signal AI-2 either by enhancing its secretion or inhibiting its uptake and consequently represses biofilm formation and motility and affects the global gene expression in biofilms [
]. TqsA exhibit a uniform topology with 8 putative transmembrane segments (TMSs), a structure shared by proteins in this family. The function of proteins in this family are mostly unknown, however, it has been suggested that they may transport a variety of compounds, possibly all related in structure []. This entry also includes transport proteins such as sodium-lithium/proton antiporter from Halobacillus [] and sporulation protein YtvI from Bacillus subtilis, a putative permease [].This entry also includes uncharacterised transmembrane protein 245 (TMEM245) from eukaryotes.
Sft2 is a non-essential membrane protein that localizes to a late-Golgi compartment and is involved in vesicle fusion with the Golgi complex [
,
]. It is thought to interact with Sed5, a yeast t-SNARE protein that plays a role in ER-Golgi and intra-Golgi vesicular transport [,
]. Sft2 and related proteins are found in eukaryotes and show four putative transmembrane regions.
Fis1 is an outer mitochondrial membrane protein that plays a role in mitochondrial membrane fission [
]. In Saccharomyces cerevisiae, it facilitates mitochondrial fission by forming protein complexes with Dnm1 and Mdv1 []. It contains tetratrico-peptide repeat (TPR)-like domain and a C-terminal transmembrane region [,
].
The mitochondrial fission protein Fis1 consists of two tetratricopeptide repeats. This entry represents the C-terminal tetratricopeptide repeat [
,
]. Fis1 is an outer mitochondrial membrane protein that plays a role in mitochondrial membrane fission [].
The mitochondrial fission protein Fis1 consists of two tetratricopeptide repeats. This entry represents the N-terminal tetratricopeptide repeat [
,
]. Fis1 is an outer mitochondrial membrane protein that plays a role in mitochondrial membrane fission [].
Pyrroline-5-carboxylate reductase (P5CR) (
) [
,
] is the enzyme that catalyses the terminal step in the biosynthesis of proline from glutamate, the NAD(P) dependent oxidation of 1-pyrroline-5-carboxylate into proline. This enzyme is also able to convert delta-1-piperideine-6-carboxylate (P6C) into pipecolic acid []; this activity is part of pathway for the biosynthesis of the cyclic tetrapeptide apicidin F in the fungus Fusarium fujikuroi []. This entry also includes the pyrroline-5-carboxylate reductase ucsG from Acremonium sp., which is part of the gene cluster that mediates the biosynthesis of UCS1025A, a member of the pyrrolizidinone family that is a strong telomerase inhibitor and displays potent antibacterial and antitumor properties [].
This family of proteins includes uncharacterised sequences from eukaryotes, cyanobacteria and Leptospira as well as the DREG-2 protein from Drosophila melanogaster (Fruit fly) which has been identified as a rhythmically (diurnally) regulated gene [
]. This family is a member of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The superfamily is defined by the presence of three short catalytic motifs []. The subfamilies are defined [] based on the location and the observed or predicted fold of a so-called, capping domain, [], or the absence of such a domain. This family is a member of subfamily 1A in which the cap domain consists of a predicted alpha helical bundle found in between the first and second catalytic motifs. A distinctive feature of this family is a conserved tandem pair of tryptophan residues in the cap domain. The most divergent sequences included within the scope of this entry are from plants and have "FW"at this position instead. Most likely, these sequences, like the vast majority of HAD sequences, represent phosphatase enzymes.
This domain is found in eukaryotic aspartyl protease DDI1 (DNA Damage Inducible protein 1; MEROPS identifier A28.001). The remarkable structural similarity between this central domain of DDI1 and the retroviral proteases suggests that DDI1 functions proteolytically during regulated protein turnover [
,
]. DDI1 has been shown to activate an endoplasmic-reticulum isoform of the transcription factor SKN-1 in Caenorhabditis elegans when the proteasome is dysfunctional []. DDI1 also has an amino-terminal ubiquitin-like domain and/or a UBA (ubiquitin-associated) domain [].
This group of sequences represent cystathionine beta-lyase (alternate name: beta-cystathionase), one of several pyridoxal-dependent enzymes of cysteine, methionine, and homocysteine metabolism. This enzyme is involved in the biosynthesis of Met from Cys.
Members of the NSCC2 family have been sequenced from various yeast, fungal and animals species including Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. These proteins are the Sec62 proteins, believed to be associated with the Sec61 and Sec63 constituents of the general protein secretary systems of yeast microsomes. They are also the non-selective cation (NS) channels of the mammalian cytoplasmic membrane. The yeast Sec62 protein has been shown to be essential for cell growth. The mammalian NS channel proteins have been implicated in platelet derived growth factor(PGDF) dependent single channel current in fibroblasts. These channels are essentially closed in serum deprived tissue-culture cells and are specifically opened by exposure to PDGF. These channels are reported to exhibit equal selectivity for Na+, K+ and Cs+ with low permeability to Ca2+, and no permeability to anions.
This is an N-terminal domain that is found adjacent to the patatin/phospholipase A2-related domain (see
) in a group of proteins. Proteins containing this domain include Tgl3/4/5 from Saccharomyces cerevisiae. Tgl3 is a bifunctional triacylglycerol lipase and lysophospholipid acyltransferase [
]. Tgl4/5 are multifunctional lipase/hydrolase/phospholipases [,
]. They are generally involved in triacylglycerol mobilisation and localized to lipid particles [,
].This entry also includes plant sugar-dependent 1 (SDP1) protein, which is a triacylglycerol lipase that initiates storage oil breakdown in germinating Arabidopsis seeds [
,
].
GUN4 is a porphyrin-binding protein involved in chlorophyll biosynthesis regulation and intracellular signaling, found in aerobic photosynthetic organisms [
,
]. It has been implicated in retrograde signalling between the chloroplast and nucleus []. GUN4 can bind protoporphyrin IX (PIX) and magnesium protoporphyrin IX (MgPIX), substrate and product of the Mg-chelatase, as well as heme and cobalt protoporphyrin IX (CoPIX) []. It may play a role in protecting plants from reactive oxygen species (ROS)-mediated damage [].
SPRING1 is a glycosylated Golgi-resident membrane protein involved in SREBP signaling and cholesterol metabolism. It modulates the proper localization of SCAP (SREBP cleavage-activating protein) to the endoplasmic reticulum, thereby controlling the level of functional SCAP [
].
This PAC2 (Proteasome assembly chaperone) family of proteins is found in bacteria, archaea and eukaryotes. Proteins in this family are typically between 247 and 307 amino acids in length. Its C-terminal segment containing the potential proteasome-activating HbYX motif. These proteins function as a chaperone for the 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass and contains one 20S core particle structure and two 19S regulatory caps. The 26S proteasome mediates ubiquitin-dependent proteolysis in eukaryotic cells. A number of studies including very recent ones have revealed that assembly of its 20S catalytic core particle is an ordered process that involves several conserved proteasome assembly chaperones (PACs). Two heterodimeric chaperones, PAC1-PAC2 and PAC3-PAC4, promote the assembly of rings composed of seven alpha subunits [,
,
,
].
This PAC2 (Proteasome assembly chaperone) family of proteins is found in bacteria, archaea and eukaryotes. Proteins in this family are typically between 247 and 307 amino acids in length. Its C-terminal segment containing the potential proteasome-activating HbYX motif. These proteins function as a chaperone for the 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass and contains one 20S core particle structure and two 19S regulatory caps. The 26S proteasome mediates ubiquitin-dependent proteolysis in eukaryotic cells. A number of studies including very recent ones have revealed that assembly of its 20S catalytic core particle is an ordered process that involves several conserved proteasome assembly chaperones (PACs). Two heterodimeric chaperones, PAC1-PAC2 and PAC3-PAC4, promote the assembly of rings composed of seven alpha subunits [
,
,
,
].This entry represents PAC2 family members found in eukaryotes.
This entry represents a group of plant multispanning transmembrane proteins that are regulated by cold. This family can be classified into two groups: the cold-regulated (COR)413-plasma membrane and COR413-thylakoid membrane groups. Proteins in this family have a highly conserved phosphorylation site and a glycosylphosphatidylinositol-anchoring site at the C-terminal end [
,
].
Polycomb group (Pc-G) proteins ensure the stable inheritance of expression
patterns through cell division and regulate the control of cell proliferation.The Enhancer of zeste (E(z))-type of Pc-G proteins includes:
Drosophila melanogaster Enhancer of zeste E(z).Mammalian ENX-1 and ENX-2.Arabidopsis thaliana CURLY LEAF (CLF), a transcriptional repressor of
floral homeotic gene AGAMOUS.Arabidopsis thaliana CLF-like.Arabidopsis thaliana MEDEA (MEA), a suppressor of endosperm development.Arabidopsis thaliana EZA1.These proteins contain a SET domain at the C terminus.Unique to them is the presence of a CXC domain, an ~65-residue cys-rich region
preceding the SET domain. The spacing of 17 cyteines is conserved. The CXCdomain contains three units of C-X(6)-C-X(3)-C-X-C motif, although the most C-
terminal unit is reverse-oriented. Because of its evolutionary conservation,the CXC domain is likely to be involved in an important function of E(z)-
related proteins [,
,
].The CXC domain shows some similarity to the CRC domain found in the tesmin/
TSO1 protein family [].
Members of this family are polycomb group (PcG) proteins from plants. They act as the catalytic subunit of some PcG multiprotein complex, which methylates 'Lys-27' of histone H3, leading to transcriptional repression of the affected target genes. These enzymes are also required to regulate floral development by repressing the AGAMOUS homeotic gene in leaves, inflorescence stems and flowers. They regulate the antero-posterior organisation of the endosperm, as well as the division and elongation rates of leaf cells. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development [
,
,
,
,
,
,
,
,
].Methyltransferases (EC [intenz:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule [,
,
]. All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM []. The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids [,
,
]. Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing [,
,
]. More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.
Diphthamide is a unique post-translationally modified histidine residue found only in translation elongation factor 2 (eEF-2). It is conserved from archaea to humans and serves as the target for diphteria toxin and Pseudomonas exotoxin A. These two toxins catalyse the transfer of ADP-ribose to diphtamide on eEF-2, thus inactivating eEF-2, halting cellular protein synthesis, and causing cell death [
]. The biosynthesis of diphtamide is dependent on at least five proteins, DPH1 to -5, and a still unidentified amidating enzyme. DPH3 and DPH4 share a conserved region, which encode a putative zinc finger, the DPH-type or CSL-type (after the the final conserved cysteine of the zinc finger and the next two residues) MB domain contains a Cys-X-Cys...Cys-X2-Cys motif which tetrahedrically coordinates both Fe and Zn. The Fe containing DPH-type MBD has an electron transfer activity [,
,
,
,
,
].This entry represents the DPH-type metal binding domain consists of a three-stranded β-sandwich with one sheet comprising two parallel strands: (i) β1 and (ii) β6 and one antiparallel strand: β5. The second sheet in the β-sandwich is comprised of strands β2, β3, and β4 running anti-parallel to each other. The two β-sheets are separated by a short stretch α-helix. It can be found in proteins such as DPH3 and DPH4. This domain is also found associated with N-terminal domain of heat shock protein DnaJ domain [
,
,
].
Phosphatidylinositol kinase (PIK)-related kinases participate in meiotic and
V(D)J recombination, chromosome maintenance and repair, cell cycleprogression, and cell cycle checkpoints, and their dysfunction can result in a
range of diseases, including immunodeficiency, neurological disorder andcancer. The catalytic kinase domain is highly homologuous to that of
phosphatidylinositol 3- and 4-kinases. Nevertheless, membersof the PIK-related family appear functionally distinct, as none of them has
been shown to phosphorylate lipids, such as phosphatidylinositol; instead,many have Ser/Thr protein kinase activity. The PI-kinase domain of members of
the PIK-related family is wedged between the ~550-amino acid-long FAT (FRAP,ATM, TRRAP) domain [
] and the ~35 residue C-terminal FATC domain [].It has been proposed that the FAT domain could be of importance as a
structural scaffold or as a protein-binding domain, or both [].The TOR1 FATC domain, in its oxidized form, consists of an α-helix and a
well structured COOH-terminal disulfide-bonded loop.Reduction of the disulfide bond dramatically increases the flexibility within
the COOH-terminal loop region. The reduction may alter the binding behavior ofFATC to its partners [
].
This domain is the central domain of AARP2 (asparagine and aspartate rich protein 2). It is weakly similar to the GTP-binding domain of elongation factor TU [
]. PfAARP2 is an antigen from Plasmodium falciparum of 150kDa, which is encoded by a unique gene on chromosome 1 []. The central region of Pfaarp2 contains blocks of repetitions encoding asparagine and aspartate residues.
This domain is found at the C terminus of the ribosome biogenesis protein BMS1 and TSR1 families, which may act as a molecular switch during maturation of the 40S ribosomal subunit in the nucleolus.
In Gram-negative organisms, PspA is part of the multi-gene Phage shock protein (Psp) response system that mitigates envelope damage by preventing proton leakage across a damaged membrane, thereby maintaining proton motive force [
]. In Mycobacterium tuberculosis, PspA has been shown to integrate envelope stress-sensing and envelope-preserving functions []. It also regulates lipid droplet homeostasis and nonreplicating persistence (NRP) in M. tuberculosis []. The PspA homologue in plants, VIPP1, plays a critical role in thylakoid biogenesis, essential for photosynthesis [].
Pyridoxal-dependent decarboxylases are bacterial proteins acting on ornithine, lysine, arginine and related substrates [
].One of the regions of sequence similarity contains a conserved lysine residue, which is the site of attachment of the pyridoxal-phosphate group. Ornithine decarboxylase is a dodecamer composed of six homodimers and catalyzes the decarboxylation of tryptophan. Arginine decarboxylase catalyzes the decarboxylation of arginine and lysine decarboxylase catalyzes the decarboxylation of lysine. Members of this family are widely found in all three forms of life [
,
,
,
,
,
,
,
,
,
,
,
,
,
].
Pyridoxal-dependent decarboxylases are bacterial proteins acting on ornithine, lysine, arginine and related substrates [
].One of the regions of sequence similarity contains a conserved lysine residue, which is the site of attachment of the pyridoxal-phosphate group. Ornithine decarboxylase is a dodecamer composed of six homodimers and catalyzes the decarboxylation of tryptophan. Arginine decarboxylase catalyzes the decarboxylation of arginine and lysine decarboxylase catalyzes the decarboxylation of lysine. Members of this family are widely found in all three forms of life [
,
,
,
,
,
,
,
,
,
,
,
,
,
].
This eukaryotic family includes a number of plant organ-specific proteins. While their function is unknown, their predicted amino acid sequence suggests that these proteins could be exported and glycosylated [].
This entry represents a group of molybdate-anion transporters, including MFSD5 (also known as hsMOT2) from humans and molybdate transporter (CrMOT2,
) from Chlamydomonas [
]. They mediate high-affinity intracellular uptake of the rare oligo-element molybdenum.
Members of this family are involved in asparagine-linked protein glycosylation. In particular, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST), also known as oligosaccharyltransferase (
), transfers the high-mannose sugar GlcNAc(2)-Man(9)-Glc(3) from a dolichol-linked donor to an asparagine acceptor in a consensus Asn-X-Ser/Thr motif. In most eukaryotes, the DDOST complex is composed of three subunits, which in humans are described as a 48kDa subunit, ribophorin I, and ribophorin II [
]. However, the yeast DDOST appears to consist of six subunits (alpha, beta, gamma, delta, epsilon, zeta). The yeast beta subunit is a 45kDa polypeptide, previously discovered as the Wbp1 protein, with known sequence similarity to the human 48kDa subunit and the other orthologues. This family includes the 48kDa-like subunits from several eukaryotes; it also includes the yeast DDOST beta subunit Wbp1.Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit Wbp1 is the beta subunit of the OST complex, one of the original six subunits purified [
]. Wbp1 is essential [,
], but conditional mutants have decreased transferase activity [,
].
The PUL (after PLAP, UFD3 and lub1) domain is a predicted predominantly alpha helical globular domain found in eukaryotes. It is found in association with either WD repeats (see
) and the PFU domain (see
) or PPPDE and thioredoxin (see
) domains. The PUL domain is a protein-protein interaction domain [
,
].Some proteins known to contain a PUL domain are listed below:Saccharomyces cerevisiae DOA1 (UFD3, ZZZ4), involved in ubiquitin conjugation pathway. DOA1 participates in the regulation of the ubiquitin conjugation pathway involving CDC48 by hindering multiubiquitination of substrates at the CDC48 chaperone.Schizosaccharomyces pombe ubiquitin homeostasis protein lub1, acts as a negative regulator of vacuole-dependent ubiquitin degradation.Mammalian phospholipase A-2-activating protein (PLA2P, PLAA), the homologue of DOA1. PLA2P plays an important role in the regulation of specific inflammatory disease processes.
The PFU (for PLAA family ubiquitin binding domain) is an ubiquitin binding domain with no homology to several known ubiquitin binding domains (e.g., UIM, NZF, UBA, UEV, UBP, or CUE domains). The PFU domain appears to be unique to the PLAA family of proteins. A single member of this family of proteins exists in every eukaryotic species examined. Each of these homologues possesses identical domain structure: an N-terminal domain containing seven WD40 repeats, a central PFU domain, and a C-terminal PUL domain, which directly binds to Cdc48, a member of the AAA-ATPase family of molecular chaperone [
]. In addition to ubiquitin, the PFU domain of DOA1 has been shown to bind to the SH3 domain [].Secondary structure predictions of the PFU domain suggest the presence of an extensive length of β-sheet, N-terminal to an α-helical region [
].Some proteins known to contain a PFU domain include:
Saccharomyces cerevisiae DOA1 (UFD3, ZZZ4), involved in the ubiquitin conjugation pathway. DOA1 participates in the regulation of the ubiquitin conjugation pathway involving CDC48 by hindering multiubiquitination of substrates at the CDC48 chaperone.Schizosaccharomyces pombe ubiquitin homeostasis protein Lub1, acts as a negative regulator of vacuole-dependent ubiquitin degradation.Mammalian phospholipase A-2-activating protein (PLA2P, PLAA), the homologue of DOA1. PLA2P plays an important role in the regulation of specific inflammatory disease processes.
Terpenes are among the largest groups of natural products and include compounds such as vitamins, cholesterol and carotenoids. The biosynthesis of all terpenoids begins with one or both of the two C5 precursors of the pathway: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In animals, fungi, and certain bacteria, the synthesis of IPP and DMAPP occurs via the well-known mevalonate pathway, however, a second, nonmevalonate terpenoid pathway has been identified in many eubacteria, algae, malaria parasite and the chloroplasts of higher plants [
,
,
].LytB(IspH) is the last enzyme in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) in the 1-deoxy-d-xylulose-5-phosphate (DOXP, the nonmevalonate pathway, also known as MEP) pathway [
]. This enzyme contains a [4Fe-4S]cluster and forms a stable complex with ferredoxin, which suggests that ferredoxin/ferredoxin-NADP+ reductase redox system serves as the physiological electron donor for LytB [
]. Escherichia coli LytB protein had been found to regulate the activity of RelA (guanosine 3',5'-bispyrophosphate synthetase I), which in turn controls the level of a regulatory metabolite. It is involved in penicillin tolerance and the stringent response [].
This domain is found in a number of known and suspected cytochrome c biogenesis proteins, including ResB [
]. Mutations in ResB indicate that they are essential for growth []. ResB is predicted to be a transmembrane protein.
