Sec-independent protein translocase protein TatA/B/E
Type:
Family
Description:
Translocation of proteins across the two membranes of Gram-negative bacteria
can be carried out via a number of routes. Most proteins marked for export carry a secretion signal at their N terminus, and are secreted by the general secretory pathway. The signal peptide is cleaved as they pass through the outer membrane. Other secretion systems include the type III system found in a select group of Gram-negative plant and animal pathogens, and the CagA system of Helicobacter pylori [
].In some bacterial species, however, there exists a system that operates
independently of the Sec pathway []. It selectively translocates periplasmic-bound molecules that are synthesised with, or are in close
association with, "partner"proteins bearing an (S/T)RRXFLK twin arginine
motif at the N terminus. The pathway is therefore termed the Twin-Arginine Translocation or TAT system. Surprisingly, the four components that make up
the TAT system are structurally and mechanistically related to a pH-dependent import system in plant chloroplast thylakoid membranes []. Thegene products responsible for the Sec-independent pathway are called TatA,
TatB, TatC and TatE.This entry represents the related TatA, TatB and TatE proteins.
This entry includes E3 ubiquitin-protein ligase Pep5 (also known as vacuolar protein sorting-associated protein 11, Vps11) from fungi, and its homologues from plants and animals. Pep5 is a peripheral vacuolar membrane protein required for protein trafficking and vacuole biogenesis [
]. It is also identified as an E3 ubiquitin ligase that regulates histone protein levels in Saccharomyces cerevisiae []. Human Vps11 may play a role in vesicle-mediated protein trafficking [].
Budding yeast Ist1 is involved in a late step in sorting of cargo proteins of the multivesicular body (MVB) for incorporation into intralumenal vesicles [
]. This entry also includes Ist1 homologues from animals and plants. Human Ist1 functions in the ESCRT (endosomal sorting complexes required for transport) pathway and is required for efficient abscission during HeLa cell cytokinesis []. Human Ist1 binds the transport (MIT) domain of VPS4, LIP5, and Spartin via its C-terminal MIT-interacting motif (MIM) [].
Vacuolar protein sorting-associated protein 13 (VPS13) is involved in the delivery of proteins to the vacuole in vegetatively growing yeast [
] and also regulates membrane morphogenesis during sporulation [,
]. It mediates the transfer of lipids between membranes at organelle contact sites [,
] and it is involved in mitochondrial lipid homeostasis [,
]. In humans, the hereditary disorders chorea acanthocytosis and Cohen syndrome are caused by mutations in members of this family that are orthologues of yeast VPS13 (VPS13A and VPS13B respectively). Human VPS13A binds phospholipids and is required for the formation or stabilization of ER-mitochondria contact sites which enable transfer of lipids between the ER and mitochondria [,
,
]. It is also required for efficient lysosomal protein degradation [].These proteins belong to the RNG superfamily (repeating β-grooves).
This entry represents vacuolar protein sorting-associated protein 35 (Vps35) from eukaryotes.
Vps35 is a core component of the retromer complex which functions in the endosome-to-Golgi retrieval cargo transport pathway [
,
]. Vps35 is part of the a cargo-selective complex trimer (CSC) of the retromer, which is composed of Vps26, Vps29 and Vps35 and is responsible for binding to and sorting protein cargo []. Mutations in the Vps35 gene have been linked to Parkinson's disease [
]. Structurally, VPS35 forms a horseshoe-shaped, right-handed, α-helical solenoid [].
Hydrogenase/Urease accessory protein HupE/UreJ protein
Type:
Family
Description:
This family of proteins are hydrogenase/urease accessory proteins. R. leguminosarum HupE is a transmembrane nickel permease that may be required for hydrogen uptake []. UreJ is a transmembrane protein shareing homology with HupE. Its function is not clear [].
Vacuolar protein sorting-associated protein Vps41/Vps8
Type:
Family
Description:
This entry includes Vps41 and Vps8.Vps41 is a subunit of the homotypic vacuole fusion and vacuole protein sorting (HOPS) complex; essential for membrane docking and fusion at the Golgi-to-endosome and endosome-to-vacuole stages of protein transport [
,
,
].Vps8 is one of the Golgi complex components necessary for vacuolar sorting [
]. Eukaryotic cells contain a highly dynamic endomembrane system, in which individual organelles keep their identity despite continuous vesicle generation and fusion. Vesicles that bud from a donor membrane are targeted and delivered to each individual organelle, where they release their cargo after fusion with the acceptor membrane. Vps8 is the core component of the endosomal tethering complex CORVET (class C core vacuole/endosome tethering). Vps8 co-operates with Vps21-GTP to mediate endosomal clustering in a reaction that is dependent on Vps3. Vps8 is the only CORVET subunit that is enriched on late endosomes, suggesting that it is a marker for the maturation of late endosomes. Late endosomes form intraluminal vesicles, and the resulting multivesicular bodies fuse with the vacuole to release their cargoes [].
TYRO protein tyrosine kinase-binding protein (Tyrobp), also called DNAX-activation protein 12 (DAP12), is expressed by NK cells and myeloid cells and mediates signalling for numerous cell-surface receptors expressed
by these cells. It has been shown to both potentiate and attenuate the activation of these cells [,
]. More than 20receptor chains have been shown to associate with DAP12. It is involved for instance in neutrophil activation mediated by integrin [
].
The VFT tethering complex (also known as GARP complex, Golgi associated retrograde protein complex, Vps53 tethering complex) is a conserved eukaryotic docking complex which is involved in recycling of proteins from endosomes to the late Golgi. Vps51 (also known as Ang2 or Vps67) is a subunit of VFT and interacts with the SNARE Tlg1 [
]. It is also part of the endosome-associated recycling protein (EARP) complex which is structurally related to GARP complex [].
ADP-ribosylation factor-like protein 2-binding protein
Type:
Family
Description:
Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses. ADP-ribosylation factor-like protein 2-binding protein, also known as BART, plays an essential role in the nuclear retention of STAT3 through interaction with GTPase ARL2 (ARF-like 2) [
]. BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 and may have a role in mitochondria transport and/or apoptosis [].
Translocation of proteins across the two membranes of Gram-negative bacteria
can be carried out via a number of routes. Most proteins marked for export carry a secretion signal at their N terminus, and are secreted by the general secretory pathway. The signal peptide is cleaved as they pass through the outer membrane. Other secretion systems include the type III system found in a select group of Gram-negative plant and animal pathogens, and the CagA system of Helicobacter pylori [
].In some bacterial species, however, there exists a system that operates
independently of the Sec pathway []. It selectively translocates periplasmic-bound molecules that are synthesised with, or are in close
association with, "partner"proteins bearing an (S/T)RRXFLK twin arginine
motif at the N terminus. The pathway is therefore termed the Twin-Arginine Translocation or TAT system. Surprisingly, the four components that make up
the TAT system are structurally and mechanistically related to a pH-dependent import system in plant chloroplast thylakoid membranes []. Thegene products responsible for the Sec-independent pathway are called TatA,
TatB, TatC and TatE.TatE is highly related to TatA and these proteins appear to overlap in functionality [
]. Translocation occurred in single mutants of either TatA or TatE, though much less efficiently, but double mutants showed no detectable translocation.
The mouse four-jointed box protein 1 (fjx1) gene and Drosophila four-jointed (fj) gene are homologues [
,
,
,
]. Fj encodes a partially secreted transmembrane (TM) type II glyco- protein. In Drosophila, the gene is a downstream target of the Notch signalling pathway in leg-segmentation and planar-cell polarity processes during eye development. Conserved in vertebrates, the murine homologue, fjx1, is also a direct target of Notch signalling [
]. The gene is expressed in mouse brain, in the peripheral nervous system, in epithelial cells of multiple organs, and during limb development [].The protein product is processed and secreted as a presumptive ligand [
]. fjx1 binding sites have been identified at complementary locations, suggesting that fjx1 may function as a novel signalling molecule [].
Vacuolar protein sorting-associated protein Vta1-like
Type:
Family
Description:
This entry represents yeast Vta1 and its homologues from animals and plants. Vta1 interacts with the AAA ATPase Vps4 and is required for multivesicular body (MVB) sorting [
,
]. This entry also includes LIP5 from Arabidopsis. LIP5 is a positive regulator of the Suppressor of K(+) Transport Growth Defect1 (SKD1) AAA ATPase in MVB biogenesis. It is also a target of pathogen-responsive mitogen-activated protein kinases (MPKs) and plays a critical role in plant basal resistance [,
]. Mammalian Vta1 homologue functions in MVB sorting and is required for HIV release [].
This entry includes bone morphogenetic protein 1 (BMP1), tolloid-like protein1/2 from mammals, dorsal-ventral patterning protein tolloid from Drosophila melanogaster, and Zinc metalloproteinase nas-39 from Caenorhabditis elegans. They are proteinases that serve as activators of a broader subset of the TGFbeta superfamily of proteins and are involved in the morphogenetic processes [
].
Vps36 is a subunit of ESCRT-II, a protein complex involved in driving protein sorting from endosomes to lysosomes. The GLUE domain of Vps36 allows for a tight interaction to occur between the protein and Vps28, a subunit of ESCRT-I. This interaction is critical for ubiquitinated cargo progression from early to late endosomes [
]. The multivesicular body (MVB) protein-sorting pathway targets transmembrane
proteins either for degradation or for function in the vacuole/lysosomes. Thesignal for entry into this pathway is monoubiquitination of protein cargo,
which results in incorporation of cargo into luminal vesicles at lateendosomes. Another crucial player is phosphatidylinositol 3-phosphate
(PtdINS(3)P), which is enriched on early endosomes and on the luminal vesiclesof MVBs. ESCRT (endosomal sorting complex required for transport)-I, -II and -III complexes are critical for MVB budding and sorting of
monoubiquitinated cargo into the luminal vesicles []. Various Ub-binding domains(UBDs), such as UIM, UEV and NZF are found in such
machineries [,
].The Vps 36 subunit of the ESCRT-II trafficking complex binds both
phosphoinositides and ubiquitin. All members of the Vps36 family contain adivergent GRAM/PH-like domain; yeast and some other fungi have one or two
NZF domains inserted in the GRAM/PH-like domain [,
].
Vacuolar protein sorting-associated protein 54 (Vps54) is a component of the GARP (Vps52/53/54) complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN) [
]. Mammalian GARP complex has been shown to play a general role in the delivery of retrograde cargo into the TGN []. In mice, a point mutation (L967Q) in the Vps54 gene causes wobbler mutation, which is characterised by degeneration of upper and lower motor neurons leading to progressive muscle weakness. The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS) [
]. Interestingly, the protein mutation (L967Q) does not prevent its integration into the GARP complex but greatly reduces the half-life and levels of the protein in vivo [].
This entry represents Vps53 from eukaryotes. Vps53 is part of the of the GARP (Golgi-associated retrograde protein) complex involved in retrograde transport from early and late endosomes to late Golgi [
,
,
]. Mutations in the human Vps53 gene cause pontocerebellar hypoplasia 2E (PCH2E), a neurodegenerative disorder characterised by progressive cerebello-cerebral atrophy, profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy [].
Vacuolar protein sorting-associated protein 9-like
Type:
Family
Description:
Proteins in this entry contain the VPS9 domain that can act as guanine nucleotide exchange factors (GEFs) against small G proteins of the Rab5 family. In budding yeasts, Vps9 is involved in vesicle-mediated vacuolar transport [
].
Translocation of proteins across the two membranes of Gram-negative bacteria
can be carried out via a number of routes. Most proteins marked for export carry a secretion signal at their N terminus, and are secreted by the general secretory pathway. The signal peptide is cleaved as they pass through the outer membrane. Other secretion systems include the type III system found in a select group of Gram-negative plant and animal pathogens, and the CagA system of Helicobacter pylori [
].In some bacterial species, however, there exists a system that operates
independently of the Sec pathway []. It selectively translocates periplasmic-bound molecules that are synthesised with, or are in close
association with, "partner"proteins bearing an (S/T)RRXFLK twin arginine
motif at the N terminus. The pathway is therefore termed the Twin-Arginine Translocation or TAT system. Surprisingly, the four components that make up
the TAT system are structurally and mechanistically related to a pH-dependent import system in plant chloroplast thylakoid membranes []. Thegene products responsible for the Sec-independent pathway are called TatA,
TatB, TatC and TatE.This entry represents Sec-independent protein translocase protein TatB (TatB) and similar proteins predominantly found in Proteobacteria. TatB is essential for the secretion of large folded proteins containing a characteristic twin-arginine motif in their signal peptide across membranes. It may form an oligomeric binding site that transiently accommodates folded Tat precursor proteins before their translocation [
]. It may form a circular arrangement with TatC [].
p53 is a tumour suppressor that suppresses tumour development by inducing stable growth arrest or cell apoptosis [
]. The expression of p53 induces the transcription of several genes, including the TP53I11 (also known as PIG11) gene, which expresses the tumor protein p53-inducible protein 11 []. The function of this protein is not clear.
Npl4 forms the Cdc48-Ufd1-Npl4 complex, which is a segregase complex that is involved in several ubiquitin-related processes. By coupling the ubiquitin-binding properties of Ufd1-Npl4 with the ATPase activity of Cdc48 (p97 in mammals), Cdc48-Ufd1-Npl4 is believed to aid in the extraction of ubiquitylated proteins from higher order complexes [
]. It also plays a role in the regulated destruction of resident ER membrane proteins [].
Dihydropteroate synthase-related protein synthase-related protein
Type:
Family
Description:
The proteins of this family have been found so far only in the four archaeal species. The central region of the proteins shows considerable homology to the amino-terminal half of dihydropteroate synthases.
This entry represents tumour protein p53-inducible nuclear protein 1 and 2 (Tp53inp1 and Tp53inp2). There is only DOR/Tp53inp2 in invertebrates, while both Tp53inp1 and Tp53inp2 can be found in vertebrates. The vertebrates Tp53inp1 gene may have arisen by gene duplication [
]. Tumour protein p53-inducible nuclear protein 1 is an antiproliferative and proapoptotic protein involved in cell stress response. It acts as a dual regulator of transcription and autophagy [
].DOR/TP53INP2 is a bifunctional protein that functions as a modulator of autophagy and in gene transcription [
].
Vacuolar protein sorting-associated protein IST1-like
Type:
Homologous_superfamily
Description:
The endosomal sorting complex required for transport (ESCRT) machinery functions in several important eukaryotic cellular processes such as MVB (multivesicular body) formation. The AAA-ATPase Vps4 catalyzes disassembly of the ESCRT-III complex and may regulate membrane deformation and vesicle scission as well. Ist1 acts as a negative regulator of the MVB pathway by binding to the N-terminal MIT (microtubule interacting and transport) domain of Vps4 through its C-terminal region, with its 15 amino acids bearing strong homology to a conserved sequence motif called MIM1 (MIT interacting motif 1 []). This MIT domain is found in various proteins and enzymes including ubiquitin hydrolases proteases, ATPases (Spastin and VPS4 proteins) and ATPase activators (Vta1p/LIP5) [].
CcmE is the product of a cluster of Ccm genes that are necessary for cytochrome c biosynthesis in many prokaryotes [
,
] and plant mitochondria []. In E. coli, expression of these proteins is induced when the organisms are grown under anaerobic conditions with nitrate or nitrite as the final electron acceptor [].
In Drosophila, Lines is a segment polarity protein and a modulator of the Abd-B HOX protein. Lines is needed for Abd-B to activate its downstream targets cut,
spalt and ems, which are involved in posterior spiracle morphogenesis [,
,
,
,
].
This entry represents RETICULATA and related proteins from plants. Arabidopsis RETICULATA protein is involved in differential development of bundle sheath and mesophyll cell chloroplasts [
].
This entry includes plant protein DMP, including Arabidopsis AtDMP1-10. DMP1 is a membrane protein that may be involved in membrane fission during breakdown of the ER and the tonoplast during leaf senescence and in membrane fusion during vacuole biogenesis in roots [
]. DMP8 and DMP9 have been shown to facilitate gamete fusion during double fertilization in flowering plants [].
This family consists of several plant proteins, including protein OCTOPUS (OPS, At3g09070) and OPSL1 (At5g01170) from Arabidopsis [
]. OPS is a membrane-associated protein that regulates phloem differentiation entry []. It is a positive regulator of the brassinosteroid (BR) signaling pathway and sequesters BIN2 to the plasma membrane to promote phloem differentiation [].
This entry represents a plant specific protein family, OBERON (OBE), also known as ptyvirus VPg-interacting protein (PVIP). In Arabidopsis, there are four OBEs, OBE1-4. OBE1 together with OBE2 are required for the maintenance and/or establishment of both the shoot and root meristems, probably by controlling the expression of the meristem genes such as WUS, PLT1 and PLT2 and of genes required for auxin responses [
]. All four OBE proteins are able to interact with OBE1 and 2. However, OBE3 and 4 do not self-interact or interact with each other []. OBE1 and OBE2 also bind to virus genome-linked proteins (VPgs) of a diverse range of potyviruses and functions as an ancillary factor to support potyvirus movement in plants []. This entry also includes protein TITANIA from rice. TITANIA is a transcriptional regulator of multiple metal transporter genes responsible for essential metals delivery to shoots for their normal growth [
]. Proteins in this family are characterised by an N-terminal domain of variable length, a central cysteine-rich region and a relatively acidic C-terminal domain. They possess a PHD-type zinc finger.
The PEBP (PhosphatidylEthanolamine-Binding Protein) family is a highly conserved group of proteins that have been identified in numerous tissues in a wide variety of organisms, including bacteria, yeast, nematodes, plants, drosophila and mammals. The various functions described for members of this family include lipid binding, neuronal development [
], serine protease inhibition [], the control of the morphological switch between shoot growth and flower structures [], and the regulation of several signalling pathways such as the MAP kinase pathway [], and the NF-kappaB pathway []. The control of the latter two pathways involves the PEBP protein RKIP, which interacts with MEK and Raf-1 to inhibit the MAP kinase pathway, and with TAK1, NIK, IKKalpha and IKKbeta to inhibit the NF-kappaB pathway. Other PEBP-like proteins that show strong structural homology to PEBP include Escherichia coli YBHB and YBCL, the Rattus norvegicus (Rat) neuropeptide HCNP, and Antirrhinum majus (Garden snapdragon) protein centroradialis (CEN). Structures have been determined for several members of the PEBP-like family, all of which show extensive fold conservation. The structure consists of a large central β-sheet flanked by a smaller β-sheet on one side, and an alpha helix on the other. Sequence alignments show two conserved central regions, CR1 and CR2, that form a consensus signature for the PEBP family. These two regions form part of the ligand-binding site, which can accommodate various anionic groups. The N- and C-terminal regions are the least conserved, and may be involved in interactions with different protein partners. The N-terminal residues 2-12 form the natural cleavage peptide HCNP involved in neuronal development. The C-terminal region is deleted in plant and bacterial PEBP homologues, and may help control accessibility to the active site.
The following proteins have been shown [
,
] to be structurally and evolutionary related:Riboflavin synthase alpha chain (
) (RS-alpha) (gene ribC in Escherichia coli, ribB in Bacillus subtilis and Photobacterium leiognathi, RIB5 in yeast. This enzyme synthesises riboflavin from two moles of 6,7- dimethyl-8-(1'-D-ribityl)lumazine (Lum), a pteridine-derivative.
Photobacterium phosphoreum lumazine protein (LumP) (gene luxL). LumP is a protein that modulates the colour of the bioluminescence emission of bacterial luciferase. In the presence of LumP, light emission is shifted to higher energy values (shorter wavelength). LumP binds non-covalently to 6,7-dimethyl-8-(1'-D-ribityl)lumazine.Vibrio fischeri yellow fluorescent protein (YFP) (gene luxY). Like LumP, YFP modulates light emission but towards a longer wavelength. YFP binds non-covalently to FMN.Aliivibrio fischeri blue fluorescence protein. These proteins seem to have evolved from the duplication of a domain of about 100 residues. In its C-terminal section, this domain contains a conserved motif [KR]-V-N-[LI]-E which has been proposed to be the binding site for lumazine (Lum) and some of its derivatives. RS-alpha which binds two molecules of Lum has two perfect copies of this motif, while LumP which binds one molecule of Lum, has a Glu instead of Lys/Arg in the first position of the second copy of the motif. Similarly, YFP, which binds to one molecule of FMN, also seems to have a potentially dysfunctional binding site by substitution of Gly for Glu in the last position of the first copy of the motif.
These proteins are found in a wide range of eukaryotes. They are nuclear proteins, suggested to play a role in the spliceosome complex [
]. XAP5 from Arabidopsis thaliana has been shown to be involved in light regulation of the circadian clock and photomorphogenesis [].
Emopamil binding protein (EBP) is a nonglycosylated type I integral
membrane protein of endoplasmic reticulum and shows high level expression in epithelial tissues. TheEBP protein has emopamil binding domains, including the sterol acceptor site and the catalytic
centre, which show Delta8-Delta7 sterol isomerase activity. Human sterol isomerase, a homologueof mouse EBP, is suggested not only to play a role in
cholesterol biosynthesis, but also to affect lipoprotein internalisation. In humans, mutations of EBPare known to cause the genetic disorder of X-linked dominant chondrodysplasia punctata (CDPX2).
This syndrome of humans is lethal in most males, and affected females display asymmetrichyperkeratotic skin and skeletal abnormalities [
].
SCAI is a transcriptional cofactor and tumour suppressor that suppresses MKL1-induced SRF transcriptional activity. It may function in the RHOA-DIAPH1 signal transduction pathway and regulate cell migration through transcriptional regulation of ITGB1 [
].
This entry includes protein patched (ptc) and protein dispatched (disp) from Drosophila melanogaster, and the Niemann-Pick C1 protein from humans. Protein patched is a receptor for the morphogene Sonic Hedgehog [
]. It associates with the smoothened protein to transduce hedgehog signals, leading to the activation of wingless, decapentaplegic and patched itself. It participates in cell interactions that establish pattern within the segment and imaginal disks during development []. The mouse homologue may play a role in epidermal development. The human Niemann-Pick C1 protein, defects in which cause Niemann-Pick type II disease, is also a member of this family. This protein is involved in the intracellular trafficking of cholesterol, and may play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural functional integrity of nerve terminals [].Protein dispatched may act by some mechanism to present or release the Hh signal for stimulation of distant target cells [
].
Arv1 is a transmembrane protein, with potential zinc-binding motifs, that mediates sterol homeostasis. Its action is important in lipid homeostasis, which prevents free sterol toxicity [
]. Arv1 contains a homology domain (AHD), which consists of an N-terminal cysteine-rich subdomain with a putative zinc-binding motif, followed by a C-terminal subdomain of 33 amino acids. The C-terminal subdomain of the AHD is critical for the protein's function []. In yeast, Arv1p is important for the delivery of an early glycosylphosphatidylinositol GPI intermediate, GlcN-acylPI, to the first mannosyltransferase of GPI synthesis in the ER lumen []. It is important for the traffic of sterol in yeast and in humans. In eukaryotic cells, it may fuction in the sphingolipid metabolic pathway as a transporter of ceramides between the ER and Golgi []. Arabidopsis thaliana has been shown to encode 2 ARV proteins (ARV1 and ARV2) both of which contain the AHD domain. This family also includes ARV2 from A. thaliana [].
This entry represents a domain found in the HABP4 protein family of hyaluronan-binding proteins, and the PAI-1 mRNA-binding protein, PAI-RBP1. HABP4 has been observed to bind hyaluronan (a glucosaminoglycan), but it is not known whether this is its primary role
in vivo. It has also been observed to bind RNA, but with a lower affinity than that for hyaluronan [
]. PAI-1 mRNA-binding protein specifically binds the mRNA of type-1 plasminogen activator inhibitor (PAI-1), and is thought to be involved in regulation of mRNA stability []. However, in both cases, the sequence motifs predicted to be important for ligand binding are not conserved throughout the family, so it is not known whether members of this family share a common function.Hyaluronan/mRNA-binding protein may be involved in nuclear functions such as the remodeling of chromatin and the regulation of transcription [
,
].
The TenA family of proteins occurs in prokaryotes, plants and fungi; it has two subfamilies, one (TenA_C) has an active-site cysteine, the other (TenA_E) doesn not. TenA_E proteins mediate amidohydrolase and aminohydrolase steps in the salvage of thiamin breakdown products [
].
In budding yeast, TIP41 interacts with TAP42 to regulate protein phosphatase activity [
]. In mammalian cells, TIP41-like protein (TIPRL) does not directly bind TAP42, but rather primarily interacts with PP2A, PP4 or PP6 catalytic subunits. TIPRL inhibits PP4 activity to allow for H2AX phosphorylation and the subsequent DNA damage response [].
This entry includes Probable splicing factor YJU2B (also known as CCDC130) and Splicing factor YJU2 (also known as CCDC94) from humans, Saf4 from fission yeasts and Yju2 from budding yeasts. Saf4 (also known as cwc16) is involved in mRNA splicing where it associates with cdc5 and the other cwf proteins as part of the spliceosome [
]. Yju2 is a splicing factor that is associated with the Prp19-associated complex and acts after Prp2 in promoting the first catalytic reaction of pre-mRNA splicing. It may play a role in stabilizing the structure of the spliceosome catalytic core [,
].
This entry represents the SAP30-binding protein that may act as a transcriptional co-repressor of a gene related to cell survival and induce cell death [
]. Proteins in this entry also include the meiotically up-regulated gene 151 protein from fission yeast [].
Twinkle protein (T7-like mitochondrial DNA helicase) is a DNA helicase needed for mitochondrial DNA replication [
]. It catalyses the ATP-dependent unwinding of a DNA duplex with 5' to 3' directionality, and it needs a single-stranded 5'-DNA and a short 3'-tail to initiate unwinding []. In humans, mutations in TWINKLE cause autosomal dominant progressive external ophthalmoplegia, a human disorder associated with multiple deletions in the mitochondrial DNA []. Arabidopsis encodes a homologue to phage T7 gp4/Twinkle proteins that has both DNA primase and DNA helicase activities [].
This family consists of various plant development proteins which are homologues of Floricaula (FLO) and leafy (LFY) proteins which are floral meristem
identity proteins.FLO and LFY proteins are floral meristem identity proteins [
,
]. Mutations in the sequences of these proteins affect flower and leaf development. LFY has been shown to bind semi-palindromic 19-bp DNA elements through its highly conserved C-terminal DNA-binding domain (DBD). In addition to its well-characterized DBD, LFY possesses a second conserved domain at its amino terminus (LFY-N). Crystallographic structure determination shows that LFY-N is a sterile alpha motif (SAM) domain that mediates LFY oligomerization. It allows LFY to bind to regions lacking high-affinity LFY-binding sites and to access closed chromatin regions. Experiments revealed that altering the capacity of LFY to oligomerize compromised floral function. It has been suggested that the biochemical properties of the SAM domain are evolutionary conserved in all plant species [].
This entry represents a family of proteins involved in the regulation of phosphatases. It includes TAP46 and TAP42, as well as others.TAP46 is involved in the positive regulation of the TOR signaling pathway in plants, acting as a negative regulator of PP2A catalytic activity [
].The TOR signalling pathway activates a cell-growth program in response to nutrients [
]. TIP41 interacts with TAP42 and negatively regulates the TOR signalling pathway [].
In budding yeasts, Mak16 forms part of the 66S pre-ribosomal particles and functions as a transacting actor involved in rRNA processing [
,
]. The Schistosoma mansoni (Blood fluke) Mak16 has been shown to target protein transport to the nucleolus [].
This family consists of selenium binding proteins from eukaryotes, bacteria and archaea. Human selenium-binding protein 1 (SELENBP1) is a methanethiol oxidase (MTO) that converts methanethiol to H2O2, formaldehyde, and H2S [
]. Bovine SBP56 has been shown to participate in late stages of intra-Golgi protein transport []. The Lotus japonicus homologue of SBP56, LjSBP is thought to have more than one physiological role, and can be implicated in controlling the oxidation/reduction status of target proteins in vesicular Golgi transport [
].
Auxin binding protein is located in the lumen of the endoplasmic reticulum (ER). The primary structure contains an N-terminal hydrophobic leader sequence of 30-40 amino acids, which could represent a signal for translocation of the protein to the ER [
,
]. The mature protein comprises around 165 residues, and contains a number of potential N-glycosylation sites. In vitro transport studies have demonstrated co-translational glycosylation []. Retention within the lumen of the ER correlates withan additional signal located at the C terminus, represented by the sequence Lys-Asp-Glu-Leu, known to be responsible for preventing secretion of proteins from the lumen of the ER in eukaryotic cells [
,
].
This entry represent LIN37 and related proteins from animals and plants. In humans, LIN37 is a component of the DREAM (MuvB/DRM) complex, which represses cell cycle-dependent genes in quiescent cells and plays a role in the cell cycle-dependent activation of G2/M genes [
,
].
Ycf54 is found encoded in the chloroplast genomes of algae, it is also found in plants and in the cyanobacteria. Ycf54 is a component of the MgPME-cyclase complex. Ycf54 plays two roles in the function of the MgPME-cyclase. First, it plays a critical role in t assembly/stability of the Mg-cyclase complex and its constituents and, secondly, is required for normal Pchlide formation. Both functions indicate that this protein is required for optimal MgPME-cyclase activity, although it is not absolutely essential [
].
Dirigent proteins impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of coniferyl alcohol in the biosynthesis of lignans, flavonolignans, and alkaloids and thus plays a central role in plant secondary metabolism [
,
]. This family also includes homologue DRR206 (disease resistance response protein 206). DRR206 is induced by the metabolite pinoresinol monoglucoside and is involved in phytoalexin (lignan) biosynthesis as a defense response [].
This family consist of the morpho-protein BolA from Escherichia coli and its various homologues. In E. coli, over-expression of this protein causes round morphology and may be involved in switching the cell between elongation and septation systems during cell division [
]. The expression of BolA is growth rate regulated and is induced during the transition into the the stationary phase []. BolA is also induced by stress during early stages of growth [] and may have a general role in stress response. It has also been suggested that BolA can induce the transcription of penicillin binding proteins 6 and 5 [,
]. IbaG is a BolA homologue involved in acid resistance [].
This family includes members from a wide variety of eukaryotes. It includes the TB2/DP1 (deleted in polyposis) protein, which in human is deleted in severe forms of familial adenomatous polyposis, an autosomal dominant oncological inherited disease [
]. REEP/DP1/Yop1 family of proteins are involved in the control of endoplasmic reticulum organisation and mutations in some members of this family are associated with inherited diseases like Hereditary spastic paraplegias (HSPs) [].The family also includes the plant protein of known similarity to TB2/DP1, the HVA22 abscisic acid-induced protein, which is thought to be a regulatory protein [
].
The Mlo-related proteins are a family of plant integral membrane proteins, first discovered in barley. Mutants lacking wild-type Mlo proteins show broad spectrum resistance to the powdery mildew fungus, and dysregulated cell death control, with spontaneous cell death in response to developmental or abiotic stimuli. Thus wild-type Mlo proteins are thought to be inhibitors of cell death whose deficiency lowers the threshold required to trigger the cascade of events that result in plant cell death. Mlo proteins are localized in the plasma membrane and possess seven transmembrane regions; thus the Mlo family is the only major higher plant family to possess 7 transmembrane domains. It has been suggested that Mlo proteins function as G-protein coupled receptors in plants that seems not to require heterotrimeric G proteins [
,
]; however the molecular and biological functions of Mlo proteins is still unclear.
This entry includes the EXORDIUM protein and related proteins. The EXO (EXORDIUM) gene was identified as a potential mediator of brassinosteroid (BR)-promoted growth [
]. It mediates cell expansion in Arabidopsis leaves []. This entry also includes PHI-1, a phosphate-induced protein of unknown function from Nicotiana tabacum [].
A number of eukaryotic proteins that seem to be involved with sterol synthesis and/or its regulation have been found [
] to be evolutionary related. These include mammalian oxysterol-binding protein (OSBP), a protein of about 800 amino-acid residues that binds a variety of oxysterols (oxygenated derivatives of cholesterol) [,
]; yeast Osh1, a protein of 859 residues that also plays a role in ergosterol synthesis []; yeast proteins Hes1 and Kes1, highly related proteins of 434 residues that seem to play a role in ergosterol synthesis [,
]; Probable transporter efuK from the fungi Hormonema carpetanum, which is involved in the biosynthesis of enfumafungin []; and OSBP-related proteins (ORP) from plants such as Arabidopsis thaliana [].
The chloroplast genomes of most higher plants contain two giant open reading frames designated ycf1 and ycf2. TIC214 is encoded by ycf1. In chloroplasts, Tic214, Tic100, Tic56, and Tic20-I form stable 1-MD TIC complexes, which were shown to associate with preproteins. TIC214 is involved in protein precursor import into chloroplasts [
]. This entry also includes some uncharacterised mitochondrial genome proteins, such as AtMg00370.
This family contains the Saccharomyces cerevisiae (Baker's yeast) HAM1 protein
and other hypothetical archaeal, bacterial and Caenorhabditis elegans proteins. S. cerevisiae HAM1 was originally identified as a gene that protects against the mutagenic effects of the base analogue 6-N-hydroxylaminopurine (HAP) which can be a natural product of monooxygenase activity on adenine [
,
]. Subsequent studies demonstrated that HAM1 detoxifies abnormal pyrimidine as well as purine nucleotides [].Similarly, a Ham1-related protein from Methanococcus jannaschii is a novel NTPase that has been shown to hydrolyze nonstandard nucleotides such as XTP to XMP and ITP to IMP, but not the standard nucleotides, in the presence of Mg or Mn ions. The enzyme exists as a homodimer [
].
Thf1 protein (also known as Psb29) is found in Cyanobacteria and in the plastids of vascular plants. They may function in the biogenesis of Photosystem II complexes [
].In Synechocystis it was isolated and partially sequenced from purified photosystem II (PS II). Deletion of psb29 in Synechocystis 6803 results in slower growth rates under high light intensities, increased light sensitivity, and lower PSII efficiency, without affecting the PSII core electron transfer activities [
]. In plants Thf1 is localised to the outer plastid membrane and the stroma. Thf1 has a role in sugar signalling. Thf1 is also thought to have a role in chloroplast and leaf development. Thf1 has been shown to play a crucial role in vesicle-mediated thylakoid membrane biogenesis [
,
].
Kinesin [
,
,
] is a microtubule-associated force-producing protein that play a role in organelle transport. The kinesin motor activity is directed toward the microtubule's plus end. Kinesin is an oligomeric complex composed of two heavy chains and two light chains. The maintenance of the quaternary structure does not require interchain disulphide bonds.This entry includes kinesin heavy chain and kinesin-like proteins, which are members of the kinesin superfamily (also known as KIFs). KIFs constitute 15 kinesin families [
]. They are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs [].
The Aux/IAA proteins are key regulators of auxin-modulated gene expression [
]. The plant hormone auxin (indole-3-acetic acid, IAA) regulates diverse cellular and developmental responses in plants, including cell division, expansion, differentiation and patterning of embryo responses []. Auxin can regulate the gene expression of several families, including GH3 and SAUR, as well as Aux/IAA itself. The Aux/IAA proteins act as repressors of auxin-induced gene expression, possibly through modulating the activity of DNA-binding auxin response factors (ARFs). Aux/IAA and ARF are thought to interact through C-terminal protein-protein interaction domains found in both Aux/IAA and ARF.Recent evidence suggests that Aux/IAA proteins can also mediate light responses [
]. Some members of the Aux/IAA family are longer and contain an N-terminal DNA binding domain [] and may have an early function in the establishment of vascular and body patterns in embryonic and post-embryonic development in some plants.
This entry represents a group of plant-specific proteins, including protein SOSEKI 1-5 from Arabidopsis thaliana and Physcomitrium patens. SOSEKI proteins (SOK1-5) integrate apical-basal and radial organismal axes to localize to polar cell edges and contain a DIX oligomerization domain that resembles that in the animal Dishevelled polarity regulator [
,
].
This family consists of defensin-like proteins from plants. Plant genomes contain several hundred defensin-like (DEFL) genes that encode short cysteine-rich proteins resembling defensins, which are known antimicrobial polypeptides [
]. Arabidopsis thaliana has more than 300 DEFL genes, and they are likely to be involved in both natural immunity and cell-to-cell communication, including pollen-pistil interactions [].
This domain is found in a family of proteins have been implicated in chlorophyll degradation [
,
]. Intriguingly members of this family are also found in non-photosynthetic bacteria.
Sec1-like molecules have been implicated in a variety of eukaryotic vesicle transport processes including neurotransmitter release by exocytosis [
].They regulate vesicle transport by binding to a t-SNARE from the syntaxin family. This process is thought to prevent SNARE complex formation, a protein complex required for membrane fusion. Whereas Sec1 molecules are essential for neurotransmitter release and other secretory events, their interaction with syntaxin molecules seems to represent a negative regulatory step in secretion [].
The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells [
,
]. These are structurally similar phospho-binding proteins that regulate multiple signaling pathways []. There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
This family is found in eukaryotes, and is approximately 60 amino acids in length. Proteins in this family contain a domain found in a group of putative lipases (
).
Protein virilizer may be involved in mRNA splicing regulation. Most of the studies on virilizer were carried out in fruit fly. In Drosophila, protein virilizer is required for male and female viability, sex determination and dosage compensation. It is involved in the female-specific splicing of Sxl transcripts. It is required for proper inclusion of regulated exons in Ubx transcripts [
,
,
].
This protein family, formerly known as DUF2511, includes Protein YebY from Escherichia coli and similar proteins predominantly found in Gammaproteobacteria. Together with YebA, encoded by the same operon, YebY is required for the activity of the copper-related NADH dehydrogenase II (NDH-2). The crystal structure of YebY shows great similarity to that of the lantibiotic self-resistance protein MlbQ, which has a hydrophobic surface patch [
,
].
Leu/Ile/Val/Thr- and Leu-binding proteins, which share a high degree of sequence similarity, are components of the leucine-specific transport system. This is one of two periplasmic binding protein-dependent systems in the high-affinity transport of branched-chain amino acids in bacteria
[,
,
]. A much weaker sequence relationship has been reported between the periplasmic binding proteins and the aliphatic amidase expression-regulating protein, AmiC. On this basis, it has been suggested that AmiC may be capable of adopting a similar 3D fold [].
PhoH is a cytoplasmic protein and predicted ATPase that is induced by phosphate starvation and belongings to the phosphate regulon (pho) in Escherichia coli [
].
This bacterial protein is predicted to be an integral membrane protein. Some family members have been annotated as transglycosylase-associated proteins, but no experimental evidence is provided. This family was annotated based on the information in
.
The RnfH family is a member of the ubiquitin superfamily. Members of the RnfH family strongly co-occur in two distinct gene neighbourhood contexts. In one it is associated with a START domain protein, a membrane protein SmpA and the transfer mRNA binding protein SmpB. This association suggests a possible role in the SmpB-tmRNA-based tagging and degradation system of bacteria, which is interesting given that other members of the ubiquitin system are analogously involved in protein-tagging and degradation across eukaryotes and various prokaryotes. The second context in which the RnfH genes are present is in a membrane associated complex involved in transporting electrons for various reductive reactions such as nitrogen fixation [
].
This entry represents SsrA-binding protein (aka small protein B or SmpB), which is a unique RNA-binding protein that is conserved throughout the bacterial kingdom and is an essential component of the SsrA quality-control system. Tight recognition of codon-anticodon pairings by the ribosome ensures the accuracy and fidelity of protein synthesis. In eubacteria, translational surveillance and ribosome rescue are performed by the 'tmRNA-SmpB' system (transfer messenger RNA-small protein B). SmpB binds specifically to the ssrA RNA (tmRNA) and is required for stable association of ssrA with ribosomes. SsrA RNA recognises ribosomes stalled on defective messages and acts to mediate the addition of a short peptide tag to the C terminus of the partially synthesised nascent polypeptide chain. Within a stalled ribosome, SmpB interacts with the three universally conserved bases G530, A1492 and A1493 that form the 30S subunit decoding centre, in which canonical codon-anticodon pairing occurs [
]. The SsrA-tagged protein is then degraded by C-terminal-specific proteases. Formation of an SmpB-SsrA complex appears to be critical in mediating SsrA activity after aminoacylation with alanine but prior to the transpeptidation reaction that couples this alanine to the nascent chain []. The SmpB protein has functional and structural similarities with initiation factor 1, and is proposed to be a functional mimic of the pairing between a codon and an anticodon.
This entry represents Protein fil from Escherichia phage 186 (Bacteriophage 186). Fil is thought to cause filamentation. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.
Proteins in this family may be involved in ovary development. Defects in POF1B are the cause of premature ovarian failure type 2B (POF2B), an ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterised by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol [
].
Mitochondria-eating protein (MIEAP, also known as spermatogenesis-associated protein 18), a p53-inducible protein, is a key regulator of mitochondrial quality that mediates the repair or degradation of unhealthy mitochondria in response to mitochondrial damage [
]. It induces intra-mitochondrial lysosome-like organella that eliminate oxidised mitochondrial proteins without destroying the mitochondrial structure, leading to improvement in mitochondrial function []. It is also involved in degradation of damaged mitochondria by promoting the formation of vacuole-like structures (named MIV), which engulf and degrade the mitochondria by accumulating lysosomes [].
Argonaute proteins are involved in RNA interference (RNAi) and microRNA (miRNA) pathways. They can be classified into three paralogous groups: Argonaute-like proteins, which are similar to Arabidopsis thaliana AGO1; Piwi-like proteins, which are closely related to D. melanogaster PIWI (P-element induced wimpy testis); and the Caenorhabditis elegans-specific group 3 Argonautes [
]. Protein argonaute-2 (AGO2) belongs to the first group (Argonaute-like proteins). It is a component of the RNA-induced silencing complex (RISC) that functions in RNA-mediated gene silencing (RNAi) [
,
]. AGO2 is the catalytic engine that drives mRNA cleavage in the RNAi pathway []. AGO2 suffers a phosphorylation cycle that is triggered by target engagement and negatively regulates target association, which is essential to maintain the global efficiency of miRNA-mediated silencing []. It is also the primary AGO variant involved in modulating expression of progesterone receptor by antigene RNAs []. AGO1 and AGO2 reside in three complexes with distinct Dicer and RNA-induced silencing complex activities []. The structure of AGO2 has been solved [].
Argonaute proteins are involved in RNA interference (RNAi) and microRNA (miRNA) pathways. They can be classified into three paralogous groups: Argonaute-like proteins, which are similar to Arabidopsis thaliana AGO1; Piwi-like proteins, which are closely related to D. melanogaster PIWI (P-element induced wimpy testis); and the Caenorhabditis elegans-specific group 3 Argonautes [
]. Protein argonaute-3 (AGO3) belongs to the first group (Argonaute-like proteins) [
]. It lacks endonuclease activity and does not appear to cleave target mRNAs []. During human stem cells proliferation, AGO3 is involved in accumulation of processed DR2 Alu transcripts and subsequent recruitment of AGO3-associated decapping complexes to the target mRNA [].
Argonaute proteins are involved in RNA interference (RNAi) and microRNA (miRNA) pathways. They can be classified into three paralogous groups: Argonaute-like proteins, which are similar to Arabidopsis thaliana AGO1; Piwi-like proteins, which are closely related to D. melanogaster PIWI (P-element induced wimpy testis); and the Caenorhabditis elegans-specific group 3 Argonautes [
]. Protein argonaute-4 (AGO4) belongs to the first group (Argonaute-like proteins) [
]. It is required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV) [].
Protein RCC2 (also known as TD-60) interacts with microtubules and is required for completion of mitosis and cytokinesis [
]. It may function as a guanine nucleotide exchange factor for the small GTPase RAC1 [].This entry also includes some uncharacterised bacterial proteins.
The PucC protein, also known as bacteriochlorophyll delivery (BCD), is required for high-level transcription of the PUC operon, essential for formation of the light harvesting complex B800-850 (LH2) of Rhodobacter capsulatus [
] as well as deliver bacteriochlorophyll a to nascent LH2 complexes.
The functions of this group of proteins are unclear. Drosophila headcase(hdc) protein is involved in dendrite pruning [
] and is a branching inhibitor during tracheal development []. It also promotes cell survival and niche maintenance in the Drosophila testis []. The human headcase protein may be part of the regulatory mechanism in the development of epithelial tube networks such as the circulatory system and lungs and may play an important role in some human cancers [].
Drosophila Fuzzy protein plays a role in the organisation of cell polarity via a planar cell polarity (PCP) cascade. It is involved in the development of the hairs on the wings [
]. Mouse Fuzzy protein is a probable planar cell polarity effector involved in cilium biogenesis. It may regulate protein and membrane transport to the cilium. It may also regulate the morphogenesis of hair follicles which depends on functional primary cilia [
,
,
].
This entry represents a conserved domain found in the N-terminal of the BTG family members (also known as anti-proliferative proteins). In mammals, BTG family comprises six proteins: BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. They regulate cell cycle progression in a variety of cell types [
].These proteins have from 158 to 363 amino acid residues, that are highly similar and include 3 conserved cysteine residues. BTG2 seems to have a
signal sequence; while the other proteins may lack such a domain.
Trypanosoma brucei is the causative agent of sleeping sickness in humans and nagana in cattle. The parasite lives extracellularly in the blood and tissue fluids of the mammalian host, and is transmitted by the bite of infected tsetse. Each variant surface glycoprotein (Vsg) expression site (ES) in bloodstream-form T. brucei is a polycistronic transcription unit containing several distinct expression site-associated genes (esag), in addition to a single vsg gene. They are co-transcribed with the gene encoding the VSG protein, forming the surface coat of the parasite. ESAG1 genes from different ESs encode a highly polymorphic family of membrane-associated glycoproteins, whose function is unknown [
].
