This family consists of several bacterial fumarate hydratase proteins FumA and FumB. Fumarase, or fumarate hydratase (EC 4.2.1.2), is a component of the citric acid cycle. In facultative anaerobes such as Escherichia coli, fumarase also engages in the reductive pathway from oxaloacetate to succinate during anaerobic growth. Three fumarases, FumA, FumB, and FumC, have been reported in E. coli. fumA and fumB genes are homologous and encode products of identical sizes which form thermolabile dimers of Mr 120,000. FumA and FumB are class I enzymes and are members of the iron-dependent hydrolases, which include aconitase and malate hydratase. The active FumA contains a 4Fe-4S centre, and it can be inactivated upon oxidation to give a 3Fe-4S centre [1].
HutD from Pseudomonas fluorescens SBW25 is a component of the histidine uptake and utilisation operon. HutD is operonic with the well characterised repressor protein HutC. Genetic analysis using transcriptional fusions (lacZ) and deletion mutants shows that hutD is necessary to maintain fitness in environments replete with histidine. Evidence outlined by Zhang & Rainey (2007) suggests that HutD functions as a governor that sets an upper bound on the level of hut operon transcription [1]. The mechanistic basis is unknown, but in silico molecular docking studies based on the crystal structure of PA5104 (HutD from Pseudomonas aeruginosa) show that urocanate (the first breakdown product of histidine) docks with the active site of HutD.
This family consists of several mammalian pro-melanin-concentrating hormone (Pro-MCH) 1 and 2 proteins. Melanin-concentrating hormone (MCH) is a 19 amino acid cyclic peptide that was first isolated from the pituitary of teleost fish. It is produced from pro-MCH that encodes, in addition to MCH, NEI, and a putative peptide, NGE. In lower vertebrates, MCH acts to regulate skin colour by antagonising the melanin-dispersing actions of small alpha, Greek-melanocyte stimulating hormone (small alpha, Greek-MSH). In mammals, MCH serves as a neuropeptide and is found in many regions of the brain and especially the hypothalamus. It affects many types of behaviours such as appetite, sexual receptivity, aggression, and anxiety. MCH also stimulates the release of luteinising hormone [1].
Family members include Autographa californica nuclear polyhedrosis virus (AcMNPV) Orf68 (also known as per os infectivity factor 6, PIF6 or ac68). PIF6 is present in both the budded virus (BV) and the occluded-derived virus (ODV). The ac68 gene overlaps the lef3 gene which encodes the single-stranded DNA binding protein, and knockout experiments of ac68 have to ensure that a functional lef3 gene is present. In ac68KO experiments, viral DNA replication and BV levels were unaffected as were mortality rates if caterpillars were injected with BV directly into the hemolymph bypassing the gut. However, in oral bioassays the ac68KO occlusion bodies failed to kill larvae, indicating that PIF6 is a per os infectivity factor [1].
The Clostridium neurotoxin family is composed of tetanus neurotoxin and seven serotypes of botulinum neurotoxin. The structure of the botulinum neurotoxin reveals a four domain protein. The N-terminal catalytic domain (Pfam:PF01742), the central translocation domains and two receptor binding domains [1]. Subsequent to cell surface binding and receptor mediated endocytosis of the neurotoxin, an acid induced conformational change in the neurotoxin translocation domain is believed to allow the domain to penetrate the endosome and from a pore, thereby facilitating the passage of the catalytic domain across the membrane into the cytosol [1]. The structure of the translocation reveals a pair of helices that are 105 Angstroms long and is structurally distinct from other pore forming toxins [1].
This family contains several bacterial MecA proteins. The development of competence in Bacillus subtilis is regulated by growth conditions and several regulatory genes. In complex media competence development is poor, and there is little or no expression of late competence genes. Mec mutations permit competence development and late competence gene expression in complex media, bypassing the requirements for many of the competence regulatory genes. The mecA gene product acts negatively in the development of competence. Null mutations in mecA allow expression of a late competence gene comG, under conditions where it is not normally expressed, including in complex media and in cells mutant for several competence regulatory genes. Overexpression of MecA inhibits comG transcription [1,2,3].
Epoxide hydrolases catalyse the hydrolysis of epoxides to corresponding diols, which is important in detoxification, synthesis of signal molecules, or metabolism. Limonene-1,2- epoxide hydrolase (LEH) differs from many other epoxide hydrolases in its structure and its novel one-step catalytic mechanism. Its main fold consists of a six-stranded mixed beta-sheet, with three N-terminal alpha helices packed to one side to create a pocket that extends into the protein core. A fourth helix lies in such a way that it acts as a rim to this pocket. Although mainly lined by hydrophobic residues, this pocket features a cluster of polar groups that lie at its deepest point and constitute the enzyme's active site [1].
This family consists of Bombinin and Maximin proteins from Bombina maxima (Chinese red belly toad). Two groups of antimicrobial peptides have been isolated from skin secretions of Bombina maxima. Peptides in the first group, named maximins 1, 2, 3, 4 and 5, are structurally related to bombinin-like peptides (BLPs). Unlike BLPs, sequence variations in maximins occurred all through the molecules. In addition to the potent antimicrobial activity, cytotoxicity against tumour cells and spermicidal action of maximins, maximin 3 possessed a significant anti-HIV activity. Maximins 1 and 3 have been found to be toxic to mice. Peptides in the second group, termed maximins H1, H2, H3 and H4, are homologous with bombinin H peptides [1].
This is the N-terminal domain found in trehalose-6-phosphate phosphatase (T6PP, EC 3.1.3.12) from parasitic nematodes such as Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. The N-terminal domain composed of a three-helix bundle is similar in topology to the Microtubule Interacting and Transport (MIT) domains of the Vps4-like ATPases from Sulfolobus acidocaldarius. MIT domains are protein-interacting domains typically associated with multivesicular body formation, cytokinetic abscission, or viral budding. Mutational analysis indicate that deletion or mutation of the MIT-like domain is highly destabilizing to the enzyme [1].
This is the C-terminal domain of BclA (Bacillus collagen-like protein of anthracis) which is expressed on spores of Bacillus species. Trimers of the C-terminal domain (CTD) form the tips of the spore's hair-like nap and are the immunodominant target of vertebrate antibodies and drive trimerization [1]. Structure analysis indicate the C-terminal region of the peptide folding into an all-beta structure with a jelly-fold topology, similar to the first human complement C1q, a member of the tumor necrosis factor (TNF)-like family. The C-terminal globular domain has been shown to be located on the exterior of the exosporium, and therefore is critical in determining the immunogenicity of the spore in a mammalian host [2].
Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse neurobiological processes including brain development, synaptogenesis, and myelination. The aGPCR GPR56/ADGRG1 regulates both oligodendrocyte and cortical development. The N-terminal domain of GPR56 has low sequence identity and a fold that likely diverged from the PTX and LNS domains. It also has a conserved motif (HphiC91xxWxxxxG) that was identified among canonical PTX domains. Thus, it is termed the Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like (PLL) domain. Truncation-based analyses suggest that the regions of GPR56 responsible for binding TG2 and collagen III are within the PLL domain, most likely in the surface-exposed conserved patch. Furthermore, it is suggested that the conserved patch of the PLL domain mediates an essential function in CNS myelination [1].
The Exodeoxyribonuclease V enzyme is a multi-subunit enzyme comprised of the proteins RecB, RecC (this family) and RecD. This enzyme plays an important role in homologous genetic recombination, repair of double strand DNA breaks resistance to UV irradiation and chemical DNA-damage. The enzyme (EC:3.1.11.5) catalyses ssDNA or dsDNA-dependent ATP hydrolysis, hydrolysis of ssDNA or dsDNA and unwinding of dsDNA [1]. This subunit recognises and binds DNA forks containing Chi sequences in a sequence specific manner while Chi interactions with the phosphodiester backbone (mainly arginine side chains) stabilise the twisted conformation of the DNA. These interactions induce conformational changes that switch RecBCD from bacteriophage destruction and CRISPR spacer acquisition, to constructive host DNA repair [2].
This family is found in Araneaea (spiders) and family members are venomus peptides with 4 disulfide bonds. Cystine knot toxins (CKTs) are small, compact molecules cross-linked by three to five disulfide bonds and are often the key contributors to the activity and potency of the venom [1]. While these disulfide-rich peptides can adopt a number of different structural motifs, three of the most observed structural scaffold motifs are the inhibitor cystine knot (ICK) and the disulfide-directed beta-hairpin (DDH) and Kunitz motif. These venomus peptides mainly act on membrane proteins in electro-excitable cell membranes by modulating voltage-activated sodium (NaV), calcium (CaV), and potassium (KV) channels, acid-sensing ion channels (ASICs), transient receptor potential (TRP) channels, and mechanosensitive channels (MSCs) [2].
Many bacteria are covered in a layer of surface-associated polysaccharide called the capsule. These capsules can be divided into four groups depending upon the organisation of genes responsible for capsule assembly, the assembly pathway and regulation [1]. This family plays a role in group 4 capsule biosynthesis [2]. These proteins have a beta-grasp fold [3]. Two beta-grasp domains, D2 and D3, are arranged in tandem. There is a C-terminal amphipathic helix which packs against D3. A helical hairpin insert in D2 binds to D3 and constrains its position, a conserved arginine residue at the end of this hairpin is essential for structural integrity [4]. This is the C-terminal domain which covers D3 and D4 domains [4].
Viral NSP8 (non structural protein 8) forms a hexadecameric supercomplex with NSP7 that adopts a hollow cylinder-like structure [1]. The dimensions of the central channel and positive electrostatic properties of the cylinder imply that it confers processivity on RNA-dependent RNA polymerase [1]. NSP7 and NSP8 heterodimers play a role in the stabilisation of NSP12 regions involved in RNA binding and are essential for a highly active NSP12 polymerase complex [2]. It has been demonstrated that NSP8 acts as an oligo(U)-templated polyadenylyltransferase but also has robust (mono/oligo) adenylate transferase activities [3]. NSP8 has N- and C-terminal D/ExD/E conserved motifs, being the N-terminal motif critical for RNA polymerase activity as these residues are part of the Mg2-binding active site [4].
Predicted to function as a sensor domain, sensing nucleotides or nucleotide derivatives generated by SMODS and other nucleotide synthetase domains [1]. This domain has been characterised in CD-NTase-associated protein 4 (Cap4), the founding member of a major family of downstream receptors that specifically respond to nucleotide second messenger signals in CBASS immunity, a bacterial system that provides immunity against bacteriophage [2,3]. SAVED exhibits divergence in its nucleotide binding pocket which enables the recognition of a wide range of CD-NTase products such as bacterial second messengers with alternative ring size, nucleobase, and 3'-5' or 2'-5' phosphodiester linkages [2]. The sensing of ligands by SAVED activates effectors that are essential for CBASS-mediated protection of bacteria from phage infection.
This entry represents the central beta-barrel domain of Integrator complex subunit 14 (IntS14), a component of the integrator complex which is involved in the transcription of small nuclear RNAs (snRNA) and their 3'-box-dependent processing. This complex is also involved in the 3'-end processing of the U7 snRNA, and the spliceosomal snRNAs U1 and U5 [1]. IntS14 interacts with IntS13, both of them consist of an N-terminal von-Willebrand type A like domain (VWA), followed by a central beta-barrel domain and a C-terminal alpha-helical domain connected through a linker. The interface involves all domains of both proteins, both beta-barrel domains form the centre of the complex and contribute to the major contact between Ints13-IntS14 [2].
Uracil-DNA glycosylase inhibitors, are DNA mimic proteins that prevent the DNA binding sites of UDGs (Uracil DNA glycosylase) from interacting with their DNA substrate. SSP0047 Swiss:Q4A134 (or SAUGI; for Staphylococcus aureus uracil-DNA glycosylase inhibitor) acts as a uracil-DNA glycosylase inhibitor that breaks the uracil-removing activity of S. aureus uracil-DNA glycosylase (SAUDG) Pfam:PF03167 [1]. The SAUGI/SAUDG complex has been determined, and shows that SAUGI binds to the SAUDG DNA binding region via several strong interactions, by using a hydrophobic pocket to hold SAUDG's protruding residue (i.e. SAUDG Leu184, E. coli UDG Leu191 and B. subtilis UDG Phe191). By binding to SAUDG in this way, SAUGI thus prevents SAUDG from binding to its DNA substrate and performing DNA repair activity [2].
This domain is found on the N-terminal region of FKBPs such as FKBP25 and in the core region of E3 ubiquitin ligase HectD1. It adopts a compact 5-helix bundle, hence termed BTHB (Basic Tilted Helix Bundle) domain. In FKBP25, it has been suggested to have a role in regulating the association state of nucleosomes by interacting with nucleolin. Moreover, this basic domain in FKBP25 forms alternative complexes with other chromatin-related proteins, such as the HDAC1, HDAC2, and the transcriptional regulator YY1, the DNA binding activity of which is enhanced on binding FKBP25. Structural analysis of this fold suggests that the DNA binding properties of FKBP25 and HectD1 are presented by the conserved basic region [1].
This annexin-like domain can be found in astrotactin 2 (Astn-2), an integral membrane perforin-like protein linked to the planar cell polarity pathway in hair cells. The annexin-like domain is closest in fold to repeat three of human annexin V and similarly binds calcium, yet shares no sequence homology with it. Notably, this ASTN-2 annexin-like domain is closer in structure to human annexin repeat 3 than human annexin repeat 3 is to repeat 1. Annexin-like domains are known for their capacity to remodel membranes, triggered by calcium binding, and have also been suggested to be involved in the formation of pores in membranes both are possible biological roles of the ASTN-2 annexin-like domain [1].
Many bacteria are covered in a layer of surface-associated polysaccharide called the capsule. These capsules can be divided into four groups depending upon the organisation of genes responsible for capsule assembly, the assembly pathway and regulation [1]. This family plays a role in group 4 capsule biosynthesis [2]. These proteins have a beta-grasp fold [3]. Two beta-grasp domains, D2 and D3, are arranged in tandem. There is a C-terminal amphipathic helix which packs against D3. A helical hairpin insert in D2 binds to D3 and constrains its position, a conserved arginine residue at the end of this hairpin is essential for structural integrity [4]. This entry represents D2 domain found at the N-terminal [4].
The AGO (Argonaute) proteins have four domains: an N-terminal domain, the PAZ domain, the MID domain and the PIWI domain. This entry is for the N-terminal domain. The N-terminal domain of AGOs is the most variable domain. Compared with prokaryotic Argonautes, KpAGO (Kluyveromyces polysporus Argonaute) has numerous surface-exposed insertion segments, with a cluster of conserved insertions re-positioning the N domain, contributing to the formation of nucleic-acid-binding channel to enable full propagation of the 3' end of the guide RNA guide-target pairing. The guide strand is used by the RISC complex to specify interactions with target RNAs. If sequence complementarity between guide and target is extensive, AGO catalyses cleavage, resulting in slicing of the target RNA [1].
This domain is functionally uncharacterised, found at the N-terminal of the uncharacterised UPF0758 proteins from bacteria and archaea, and is approximately 90 amino acids in length. UPF0758 was previously known as the radC family, a name that was assigned according to the radC102 mutant of E. coli which was later demonstrated to be an allele of the transcription-repair-coupling factor recG [1, 2]. UPF0758 has been described as a putative JAMM-family deubiquitinating enzyme, but its function remains to be determined [3]. Structure prediction using Colab notebook from AlphaFold DB suggests that it has an alpha bundle fold. It may contain two helix-hairpin-helix (HhH) motifs. This domain is found in association with Pfam:PF04002 [4].
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 maturated 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 [2,3,4]. The crystal structure of the protein from Aquifex aeolicus showed an overall fold consisting of one central alpha-helix surrounded by a four-stranded beta-sheet and four other alpha-helices [5].
This domain represents one of the two dimerisation regions of the protein, located at the edge of the dimer interface, at the C-terminus, being the last three beta strands, S6, S7, and S8 along with the last three residues to the end. In Swiss:P21159, S6 runs from residues 178-192, S7 from 200-206 and S8 from 211-215. the extended loop, of residues 167-177 may well be involved in the pocket formed between the two dimers that positions the FMN molecule [1].To date, the only time functional oxidase or phenazine biosynthesis activities have been experimentally demonstrated is when the sequences contain both Pfam:PF01243 and Pfam:PF10590. It is unknown the role performed by each domain in bringing about molecular functions of either oxidase or phenazine activity [2].
Members of this family adopt a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive beta-hairpins (beta 1 to beta 4). An approx. 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, the alpha 9 and alpha 10 helices pack with BRCA-2_OB1 (Pfam:PF09103) through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. The domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome [1].
This family is found towards the C-terminus of the DEAD-box helicases (Pfam:PF00270). In these helicases it is apparently always found in association with Pfam:PF04408. There do seem to be a couple of instances where it occurs by itself - e.g. Swiss:Q84VZ2. The structure PDB:3i4u adopts an OB-fold. helicases (Pfam:PF00270). In these helicases it is apparently always found in association with Pfam:PF04408. This C-terminal domain of the yeast helicase contains an oligonucleotide/oligosaccharide-binding (OB)-fold which seems to be placed at the entrance of the putative nucleic acid cavity. It also constitutes the binding site for the G-patch-containing domain of Pfa1p. When found on DEAH/RHA helicases, this domain is central to the regulation of the helicase activity through its binding of both RNA and G-patch domain proteins [1].
The BRCT domain is found predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain of XRCC1 forms a homodimer in the crystal structure. This suggests that pairs of BRCT domains associate as homo- or heterodimers. BRCT domains are often found as tandem-repeat pairs [2]. Structures of the BRCA1 BRCT domains revealed a basis for a widely utilised head-to-tail BRCT-BRCT oligomerisation mode [3]. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. Disease associated missense and nonsense mutations in the BRCA1 BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants [5].
This family consists of the 116kDa V-type ATPase (vacuolar (H+)-ATPases) subunits, as well as V-type ATP synthase subunit i. The V-type ATPases family are proton pumps that acidify intracellular compartments in eukaryotic cells for example yeast central vacuoles, clathrin-coated and synaptic vesicles. They have important roles in membrane trafficking processes [1]. The 116kDa subunit (subunit a) in the V-type ATPase is part of the V0 functional domain responsible for proton transport. The a subunit is a transmembrane glycoprotein with multiple putative transmembrane helices it has a hydrophilic amino terminal and a hydrophobic carboxy terminal [1,2]. It has roles in proton transport and assembly of the V-type ATPase complex [1,2]. This subunit is encoded by two homologous gene in yeast VPH1 and STV1 [2].
Family of endo-beta-N-glucuronidase, or heparanase. Heparan sulfate proteoglycans (HSPGs) play a key role in the self- assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular micro-environment. Heparanase degrades HS at specific intra-chain sites. The enzyme is synthesised as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. Experimental evidence suggests that heparanase may facilitate both tumour cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity [1].
Apc1 is the largest of the subunits of the anaphase-promoting complex or cyclosome. The anaphase-promoting complex is a multiprotein subunit E3 ubiquitin ligase complex that controls segregation of chromosomes and exit from mitosis in eukaryotes [1,2]. Infection of human fibroblasts with human cytomegalovirus (HCMV) leads to cell cycle dysregulation, which is associated with the inactivation of the anaphase-promoting complex [3]. Apc1 consists of a N-terminal WD40 beta-propeller domain, a middle domain (Mid-N), a PC domain and a C-terminal domain (Mid-C) that coalesces with Mid-N to form Apc1Mid which connects Apc1-WD40 with Apc1-PC and comprises an alpha-solenoid capped by a beta-sandwich [4,5]. The N-terminal domain is essential for APC/C catalytic activity as it mediates the coactivator-induced conformational change of the APC/C which promotes UbcH10 binding [4].
This family of class II histone deacetylase complex subunits HDA2 and HDA3 is found in fungi, The member from S. pombe is referred to as Ccq1 in Swiss:Q10432. These proteins associate with HDA1 to generate the activity of the HDA1 histone deacetylase complex. HDA1 interacts with itself and with the HDA2-HDA3 subcomplex to form a probable tetramer and these interactions are necessary for catalytic activity. The HDA1 histone deacetylase complex is responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. HDA2 and HDA3 have a conserved coiled-coil domain towards their C-terminus [1].
YihI activates the GTPase activity of Der, a 50S ribosomal subunit stability factor [1]. The stimulation is specific to Der as YihI does not stimulate the GTPase activity of Era or ObgE. The interaction of YihI with Der requires only the C-terminal 78 amino acids of YihI [1]. A yihI deletion mutant is viable and shows a shorter lag period, but the same post-lag growth rate as a wild-type strain. yihI is expressed during the lag period. Overexpression of yihI inhibits cell growth and biogenesis of the 50S ribosomal subunit [1]. YihI is an unusual, highly hydrophilic protein with an uneven distribution of charged residues, resulting in an N-terminal region with high pI and a C-terminal region with low pI [1].
This family contains sequences that are similar to the fatty acid metabolism regulator protein (FadR, Swiss:P09371). This functions as a dimer, with each monomer being composed of an N-terminal DNA-binding domain and a regulatory C-terminal domain. A linker comprising two short alpha helices joins the two domains. In the C-terminal domain, an antiparallel array of six alpha helices forms a barrel-like structure, while a seventh alpha helix forms a 'lid' at the end closest to the N-terminal domain. This structure was found to be similar to that of the C-terminal domain of the Tet repressor. Long-chain acyl-CoA thioesters interact directly and reversibly with the C-terminal domain, and this interaction affects the structure and therefore the DNA binding properties of the N-terminal domain [1].
This family is one of the subunits of the TRAPP Golgi trafficking complex [1]. TRAPP subunits are found in two different sized complexes, TRAPP I and TRAPP II. While both complexes contain the same seven subunits, Bet3p, Bet5p, Trs20p, Trs23p, Trs31p, Trs33p and Trs85p, with TRAPPC human equivalents, TRAPP II has the additional three subunits ,Trs65p, Trs120p and Trs130p [3]. While it has been implicated in cell wall biogenesis and stress response, the role of Trs65 in TRAPP II is supported by the findings that the protein co-localises with Trs130p, and deletion of TRS65 in yeast leads to a conditional lethal phenotype if either one of the other TRAPP II-specific subunits is modified [4]. Furthermore, the trs65 mutant has reduced Ypt31/32p guanine nucleotide exchange, GEF, activity [3].
Adenoviruses express up to 20 distinct mRNAs from five major late transcription unit (MLTU) regions, L1 to L5. The L4 region expresses L4-33K and a related protein, L4-22K [1]. L4-22K and L4-33K have complementary but not redundant functions that provide the normal pattern of mRNA production during the late phase of infection [1]. L4-33K is an alternative RNA splicing factor that up-regulates several MLTU splice acceptor sites as the late phase progresses [1,2]. L4-22K plays a role in genome packaging via its binding, in association with IVa2, to the A2 sequence within the packaging signal [3]. Additionally, L4-22K plays an important role in the temporal switch from the early to late phase of infection by regulating both early and late gene expression [4,5].
Type IIS restriction endonuclease FokI is a member of an unusual class of bipartite restriction enzymes that recognises the double-stranded DNA sequence 5'-GGATG-3' and cleave DNA phosphodiester groups 9 base pairs away on this strand and 13 base pairs away on the complementary strand [1]. FokI contains amino- and carboxy-terminal domains corresponding to the DNA- recognition and cleavage functions, respectively. The recognition domain is made of three smaller subdomains (D1, D2 and D3) which are evolutionarily related to the helix-turn-helix- containing DNA-binding domain of the catabolite gene activator protein CAP [3]. This entry represents the subdomain D1 of FokI. Subdomain D1 of the recognition domain covers the DNA major groove, recognizing base pairs at the 3' end of the recognition sequence (GGATG) [3].
This family is the toxin of a type 1 toxin-antitoxin system which is found in a relatively widespread range of bacterial species. The species distribution suggests frequent horizontal gene transfer. In a type 1 system, as characterised for the plasmid-encoded E coli hok/sok system, the toxin-encoding stable mRNA encodes a protein which rapidly leads to cell death unless the translation is suppressed by a short-lived small RNA. The plasmid-encoded module prevents the growth of plasmid-free offspring, thus ensuring the persistence of the plasmid in the population. Plasmid-free cells arising after cell-division will be killed because the stable mRNA toxin is present while the comparably unstable anti-toxin is rapidly degraded. Where the system is transcribed chromosomally, the mechanism is poorly understood [1].
This domain is the 70 C-terminal residues of ADAP - Adhesion and de-granulation promoting adapter protein. It shows homology to SH3 domains; however, conserved residues of the fold are absent. It thus represents an altered SH3 domain fold. An N-terminal, amphipathic, helix makes extensive contacts to residues of the regular SH3 domain fold thereby creating a composite surface with unusual surface properties. The domain can no longer bind conventional proline-rich peptides [1]. There are key phosphorylation sites within the two hSH3 domains and it would appear that binding at these sites does not materially affect the folding of these regions although the equilibrium towards the unfolded state may be slightly altered [2]. The binding partners of the hSH3 domains are still unknown [2].
WYL is a Sm-like SH3 beta-barrel fold containing domain. It is a member of the WYL-like superfamily, named for three conserved amino acids found in a subset of the superfamily. However, these residues are not strongly conserved throughout the family. Rather, the conservation pattern includes four basic residues and a position often occupied by a cysteine [1], which are predicted to line a ligand-binding groove typical of the Sm-like SH3 beta-barrels. A WYL domain protein (sll7009) is a negative regulator of the I-D CRISPR-Cas system in Synechocystis sp [2]. It is predicted to be a ligand-sensing domain that could bind negatively charged ligands, such as nucleotides or nucleic acid fragments, to regulate CRISPR-Cas and other defense systems such as the abortive infection AbiG system.
A papain fold toxin domain found in bacterial polymorphic toxin systems. In these systems they might function either as a releasing peptidase or toxin [1]. In Shigella flexneri, UniProtKB:Q8VSD5, this protein is expressed from a plasmid, and delivered into the host via the type III secretion system where it deamidates the glutamine residue at position 100 in ubiquitin-activating enzyme E2, UBC13, to a glutamic acid residue. Invasion of host cells by pathogens normally invokes an acute inflammatory response through activating the TRAF6-mediated signalling pathway. UBC13 helps to activate TRAF6. Thus deamidation of UBC13 results in the dampening of the inflammatory response. The key glutaminase deamidase activity is mediated by a cys-his-glu triad, present in all members of the family [2,3].
Apelin is among the most potent stimulators of cardiac contractility known. The apelin-APJ signaling pathway is an important novel mediator of cardiovascular control [1]. Apelin is an adipokine secreted by adipocytes where it is co-expressed with apelin receptor (APJ) in adipocytes. It suppresses adipogenesis through MAPK kinase/ERK dependent pathways and prevents lipid droplet fragmentation, thereby inhibiting basal lipolysis through AMP kinase dependent enhancement of perilipin expression. It also inhibits hormone-stimulated acute lipolysis through decreasing perilipin phosphorylation. Apelin induces a decrease of free fatty acid release via its dual inhibition on adipogenesis and lipolysis [2]. As a vaso-active and vascular cell growth-regulating peptide Apelin is a target of the BMP pathway, the TGF-beta/bone morphogenic protein (BMP) system - a major pathway for angiogenesis [3].
Terminase large subunit (TerL) from bacteriophages and evolutionarily related viruses, is an important component of the DNA packing machinery and comprises an ATPase domain, which powers DNA translocation and a nuclease domain that cuts concatemeric DNA [1,2]. TerL forms pentamers in which the ATPase domains form a ring distal to the capsid. This is the ATPase domain which contains a C-terminal subdomain that sits above the ATPase active site, called the "Lid subdomain" with reference to analogous lid subdomains found in other ATPases [3]. It contains a hydrophobic patch (Trp and Tyr residues) that mediates critical interactions in the interface between adjacent ATPase subunits and assists the positioning of the arginine finger residue that catalyses ATP hydrolysis [2,3]. This entry also includes bacterial proteins of unknown function.
Vacuolar H+-ATPase (V-ATPase) is a ubiquitous multi-subunit proton pump that acidifies a wide variety of intracellular compartments, which in turn affects many biological processes, including membrane trafficking, protein degradation and coupled transport of small molecules and pH homeostasis. Subunit 'a' of V0 (the functional domain responsible for proton transport) sector is highly conserved across eukaryotic species and exists in multiple isoforms. It is the largest subunit of V-ATPases and partitioned almost equally into an N-terminal cytosolic domain and a C-terminal integral membrane. Structure analysis of the N-terminal cytosolic domain from the Meiothermus ruber subunit 'I' homolog of subunit a shows that it is composed of a curved long central alpha-helix bundle capped on both ends by two lobes with similar alpha/beta architecture [1].
This domain is found in ATP-dependent DNA helicase RecG from bacteria the homologue from Arabidopsis, which has a critical role in recombination and DNA repair. This protein comprises three structural domains, the largest N-terminal Domain 1 which interacts with DNA junctions, and Domains 2 and 3 at the C-terminal which contain the characteristic motifs that identify RecG as an SF2 helicase. This domain represents the C-terminal of Domain 3. Around 50 residues that extend from its end cross back to Domain 1 forming a hook that wraps around the extended alpha-helix. This interaction provides a link between Domain 1 and 3 and it is likely that these residues are involved in conformational changes associated with domain movements arising from ATP binding and hydrolysis [1].
Intimin and its translocated intimin receptor (Tir) are bacterial proteins that mediate adhesion between mammalian cells and attaching and effacing (A/E) pathogens. A unique and essential feature of A/E bacterial pathogens is the formation of actin-rich pedestals beneath the intimately adherent bacteria and localised destruction of the intestinal brush border. The bacterial outer membrane adhesin, intimin, is necessary for the production of the A/E lesion and diarrhoea. The A/E bacteria translocate their own receptor for intimin, Tir, into the membrane of mammalian cells using the type III secretion system. The translocated Tir triggers additional host signalling events and actin nucleation, which are essential for lesion formation [1]. This family represents the Tir N-terminal domain which is involved in Tir stability and Tir secretion [2].
This domain is found in Fanconi-anemia-associated nuclease 1 (FAN1) present in Pseudomonas aeruginosa. FAN1 is a nuclease associated with Fanconi anemia (FA), an autosomal recessive genetic disorder caused by defects in FA genes responsible for processing DNA inter-strand cross-links (ICLs). The domain, known as the SAP domain, helps to augment the overall protein DNA interaction by interacting with the 3' and 5' ends of the template strand. Support of the pre-nick segment binding is crucial as multiple mutations in this domain resulted in hypersensitivity to a cross-linking agent in the SAP domain of Caenorhabditis elegans' FAN1. The helix-hairpin-helix of the SAP recognize three consecutive phosphate groups (C19, A20 and A21) at the 3' end of the template via the basic residues K116, K135 and K117 [1].
This domain is found in Monalysin Pore-forming Toxin which is a type of beta-barrel pore-forming toxin protein found in Pseudomonas entomophila. Monalysin forms a stable doughnut-like 18-mer complex composed of two disk-shaped nonamers to form a pore. The domain is composed of a central twisted beta -sheet composed of three antiparallel beta-strands (beta 3, beta 6, and beta 8/9) and flanked by the pore-forming segment and the C-terminal region on either side. The pore-forming domain (residues 102-170) is located between strands beta 3 and beta 6, and is formed from two antiparallel beta-strands connected by three alpha-helices, alpha 3, alpha 4, and alpha 5. The C-terminal region forms a long alpha-helix followed by a small hairpin and a short alpha-helix [1].
Phage holins and lytic enzymes are both necessary for bacterial lysis and virus dissemination. This family also includes TcdE/UtxA involved in toxin secretion in Clostridium difficile [1]. The 1.E.10 family is represented by Bacillus subtilis phi29 holin [2,3]; 1.E.16 represents the Cph1 holin[4]; and the 1.E.19 family is represented by the Clostridium difficile TcdE holin. Toxigenic strains of C. difficile produce two large toxins (TcdA and TcdB) encoded within a pathogenicity locus. tcdE, encoded between tcdA and tcdB, encodes a 166 aa protein which causes death to E. coli when expressed, and the structure of TcdE resembles holins. TcdE acts on the bacterial membrane. Since TcdA and TcdB lack signal peptides, they may be released via TcdE either prior to or subsequent to cell lysis [1].
Astrotactin-1 and 2 (ASTN1/2) are integral membrane proteins with a large C-terminal domain, extracellular for ASTN1 and endosome luminal for ASTN-2 [1,2]. They play critical roles in neurodevelopment, and ASTN-2 is also involved in the planar cell polarity pathway in hair cells. This is a domain found in the middle of the C-terminal of ASTN-1 and 2, which comprises a EGF- like domain (EGF4) and a fibronectin type III (Fn(III)) domain [1]. These subdomains are located between the MACPF and annexin- like domains. The structure of Fn(III) from ASTN2 revealed an unexpected feature which has two additional beta strands folded across the core. The junction between EGF-4 and Fn(III) domains in ASTN2 (but not in ASTN1) is thought to be an inositol triphosphate binding site [1].
The Golgi enzyme UDP-GlcNAc-lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase), an alpha2beta2gamma2 hexamer, mediates the initial step in the addition of the mannose 6-phosphate targeting signal on newly synthesized lysosomal enzymes [1]. GNPTAB encodes the alpha and beta subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III alpha-beta The alpha-beta subunits contain three identifiable domains separated by so-called spacer regions. This domain is part of the first spacer region, Spacer-1 [2]. Studies indicate that GlcNAc-1 lacking spacer-1 exhibits enhanced phosphorylation of several non-lysosomal glycoproteins, while the phosphorylation of lysosomal acid hydrolases is not altered. In view of these effects on the maturation and function of GlcNAc-1, it is suggested to rename 'spacer-1' the 'regulatory-1' domain [1].
This is a cys-rich region (CRR) domain found in PriA DNA helicases. In bacteria, the replication restart process is orchestrated by the PriA DNA helicase, which identifies replication forks via structure-specific DNA binding and interactions with fork-associated ssDNA-binding proteins (SSBs). The CRR region which is embedded within the C-terminal helicase lobe has been identified to bind two Zn2+ ions. This 50-residue insertion forms a structure on the surface of the helicase core in which two Zn2+ ions are coordinated by invariant Cys residues. Biochemical experiments have shown that sequence changes to Zn2+-binding Cys residues in the PriA CRR can eliminate helicase, but not ATPase, activity and can block assembly of PriB onto DNA-bound PriA, implicating the CRR in multiple functions in PriA [1].
The KH-like domain at the C-terminus of the EngA subfamily of essential bacterial GTPases has a unique domain structure position. The two adjacent GTPase domains (GD1 and GD2), two domains of family MMR_HSR1, Pfam:PF01926, pack at either side of the C-terminal domain. This C-terminal domain resembles a KH domain but is missing the distinctive RNA recognition elements. Conserved motifs of the nucleotide binding site of GD1 are integral parts of the GD1-KH domain interface, suggesting the interactions between these two domains are directly influenced by the GTP/GDP cycling of the protein. In contrast, the GD2-KH domain interface is distal to the GDP binding site of GD2. This family has not been added to the KH clan since SCOP classifies it separately due to its missing the key KH motif/fold.
This entry represents the Walker B domain of RAD50 from eukaryotes and the prokaryotic homologue SbcCD complex subunit C. RAD50-ATPase forms a complex with Mre11-nuclease that detects and processes diverse and obstructed DNA ends. This domain is separated of the Walker A domain by a long coiled-coil domain and forms the nucleotide-binding domain (NBD) when the coiled coils fold back on themselves and bring together Walker A and B domains [1,2,3,4]. Two RAD50-NBDs forms heterotetramers with a Mre11 nuclease dimer that assemble as catalytic head module that binds and cleaves DNA in an ATP-dependent reaction. Through secondary structural analysis, it has been suggested that there is a wide structural conservation in the Rad50/SMC protein family as seen in structural similarities between RAD50's hook and ABC-ATPase MukB's elbow region [4].
This is a conserved region from DNA primase. This corresponds to the Toprim domain common to DnaG primases, topoisomerases, OLD family nucleases and RecR proteins [1]. Both DnaG motifs IV and V are present in the alignment, the DxD (V) motif may be involved in Mg2+ binding and mutations to the conserved glutamate (IV) completely abolish DnaG type primase activity [1]. DNA primase EC:2.7.7.6 is a nucleotidyltransferase it synthesises the oligoribonucleotide primers required for DNA replication on the lagging strand of the replication fork; it can also prime the leading stand and has been implicated in cell division [2]. This family also includes the atypical archaeal A subunit from type II DNA topoisomerases [4]. Type II DNA topoisomerases catalyse the relaxation of DNA supercoiling by causing transient double strand breaks.
This is the DYW domain found in nucleic acid deaminases prototyped by the plant PPR DYW proteins that are implicated in chloroplast and mitochondrial RNA transcript maturation by numerous C to U editing events [1,3,4]. The name derives from the DYW motif present at the C-terminus of the classical plant PPR DYW deaminases. Members containing this domain are present in bacteria, plants, Naegleria, and fungi [2]. Plants and Naegleria show lineage-specific expansions of this family. This domain contains a characteristic zinc-binding motif (CXXC, HXE) which has been shown to bind zinc ions. This domain is often fused to PPR repeats. Ascomycete versions, which are independent lateral transfers, contain a large insert within the domain and are often fused to ankyrin repeats. Bacterial versions are predicted to function as toxins in polymorphic toxin systems [2].
gpW is a 68 residue protein known to be present in phage particles. Extracts of phage-infected cells lacking gpW contain DNA-filled heads, and active tails, but no infectious virions. gpW is required for the addition of gpFII to the head, which is, in turn, required for the attachment of tails. Since gpFII and tails are known to be attached at the connector, gpW is also likely to assemble at this site. The addition of gpW to filled heads increases the DNase resistance of the packaged DNA, suggesting that gpW either forms a plug at the connector to prevent ejection of the DNA, or binds directly to the DNA. The large number of positively charged residues in gpW (its calculated pI is 10.8) is consistent with a role in DNA interaction [1].
Escherichia coli endonuclease III (EC 4.2.99.18) [1] is a DNA repair enzyme that acts both as a DNA N-glycosylase, removing oxidised pyrimidines from DNA, and as an apurinic/apyrimidinic (AP) endonuclease, introducing a single-strand nick at the site from which the damaged base was removed. Endonuclease III is an iron-sulfur protein that binds a single 4Fe-4S cluster. The 4Fe-4S cluster does not seem to be important for catalytic activity, but is probably involved in the proper positioning of the enzyme along the DNA strand [2]. The 4Fe-4S cluster is bound by four cysteines which are all located in a 17 amino acid region at the C-terminal end of endonuclease III. A similar region is also present in the central section of mutY and in the C-terminus of ORF-10 and of the Micro-coccus UV endonuclease [4].
This is the second N-terminal domain, NII domain, of the DNA polymerase III polC subunit A that is found only in Firmicutes. DNA polymerase polC-type III enzyme functions as the 'replicase' in low G + C Gram-positive bacteria [1]. Purine asymmetry is a characteristic of organisms with a heterodimeric DNA polymerase III alpha-subunit constituted by polC which probably plays a direct role in the maintenance of strand-biased gene distribution; since, among prokaryotic genomes, the distribution of genes on the leading and lagging strands of the replication fork is known to be biased [2]. It has been predicted that the N-terminus of polC folds into two globular domains, NI and NII. A predicted hydrophobic surface patch suggests this domain may be involved in protein binding [3]. This domain is associated with DNA_pol3_alpha Pfam:PF07733 and DNA_pol3_a_NI Pfam:PF14480.
This domain of about 280 residues is found in eukaryotes. There are two conserved sequence motifs: GFC and GLL. This family is also known as UPF0704. This domain is found FAP206 Swiss:Q23H79, a protein associated with cilia and flagella. In the ciliate Tetrahymena, the cilium has radial spokes, each of which is a macromolecular complex essential for motility. A triplet of three radial spokes, RS1, RS2, and RS3, is repeated every 96 nm along the doublet microtubule. Each spoke has a distinct base that docks to the doublet and is linked to different inner dynein arms. Knockout of the FAP206 gene results in slow cell motility and the 96-nm repeats lack RS2 and dynein c. FAP206 is probably part of the front prong and docks RS2 and dynein c to the microtubule [1].
CoA-transferases are found in organisms from all lines of descent. Most of these enzymes belong to two well-known enzyme families, but recent work on unusual biochemical pathways of anaerobic bacteria has revealed the existence of a third family of CoA-transferases. The members of this enzyme family differ in sequence and reaction mechanism from CoA-transferases of the other families. Currently known enzymes of the new family are a formyl-CoA: oxalate CoA-transferase, a succinyl-CoA: (R)-benzylsuccinate CoA-transferase, an (E)-cinnamoyl-CoA: (R)-phenyllactate CoA-transferase, and a butyrobetainyl-CoA: (R)-carnitine CoA-transferase. In addition, a large number of proteins of unknown or differently annotated function from Bacteria, Archaea and Eukarya apparently belong to this enzyme family. Properties and reaction mechanisms of the CoA-transferases of family III are described and compared to those of the previously known CoA-transferases.
A member of the nucleic acid/nucleotide deaminase superfamily prototyped by Orientia OTT_1508 [1]. Members of this family are present in a wide phyletic range of bacteria,including several intracellular parasites and eukaryotes such as fungi, Leishmania, Selaginella, and some apicomplexa. In bacteria, these deaminases are predicted to function as toxins in bacterial polymorphic toxin systems [1]. Versions in intracellular bacteria lack immunity proteins and are likely to be deployed against their eukaryotic hosts. Eukaryotic versions are predicted to function as nucleic acid (either DNA or RNA) deaminases. Among eukaryotes, some fungi show lineage-specific expansions of this family. Many fungal versions are fused to a distinct N-terminal globular domain. Various fungal versions are fused to domains involved in chromatin function. Apicomplexan versions are fused to tRNA guanine transglycosylase domain [1].
This is C-terminal domain (CTD) of M60-peptidases Pfam:PF13402 [1]. It Can also be found at the C-terminal region of gingipain B (RgpB) from P. gingivalis. It was found to possess a typical Ig-like fold encompassing seven antiparallel beta-strands organized in two beta-sheets, packed into a beta-sandwich structure that can spontaneously dimerise through C-terminal strand swapping. Translocation of gingipains from the periplasm across the OM is dependent on the conserved CTD, which appears to be important for secretion of the proteins and in particular, truncation of the last few C-terminal residues of this domain leads to accumulation of gingipains in the periplasm. Subsequently, the T9SS targeting signal was demonstrated to reside within the last 22 residues at the C-terminus of the CTD. During gingipain translocation across the OM, the CTD is cleaved off by PorU [2].
This family consists of the N-terminal region of several mammalian and one bird sequence from Gallus gallus (Chicken). All of the mammalian proteins are hypothetical and have no known function but Swiss:Q8JG54 from the chicken is annotated as being a repulsive guidance molecule (RGM). RGM is a GPI-linked axon guidance molecule of the retinotectal system. RGM is repulsive for a subset of axons, those from the temporal half of the retina. Temporal retinal axons invade the anterior optic tectum in a superficial layer, and encounter RGM expressed in a gradient with increasing concentration along the anterior-posterior axis. Temporal axons are able to receive posterior-dependent information by sensing gradients or concentrations of guidance cues. Thus, RGM is likely to provide positional information for temporal axons invading the optic tectum in the stratum opticum [1].
Heliorhodopsins, distantly related to type-1 rhodopsins, are embedded in the membrane with their N termini facing the cell cytoplasm, an orientation that is opposite to that of type-1 or type-2 rhodopsins. Heliorhodopsins show photocycles that are longer than one second, which is suggestive of light-sensory activity. Heliorhodopsin photocycles accompany retinal isomerization and proton transfer, as in type-1 and type-2 rhodopsins, but protons are never released from the protein [1].The structures of several heliorhodopsins have been solved displaying seven transmembrane helices (TM), six loops and short N and C termini [2,3]. Heliorhodopsins share a common fold with the type-1 rhodopsins, however there are clear structural differences, particularly within the loop regions and the large cavity in the cytoplasmic part of heliorhodpsin [2,3]. Heliorhodpsins are present in Archaea, Bacteria, Eukarya, and viruses [3].
This is the C-terminal SH3-like domain which can be found in the exoribonuclease Xrn1. Xrn1 is a 175 kDa processive exoribonuclease that is conserved from yeast to mammals which targets cytoplasmic RNA substrates marked by a 5' monophosphate for processive 5'-to-3' degradation. The Sh3-like domain in Xrn1 lacks the canonical SH3 residues normally involved in binding proline-rich peptide motifs and instead engages in non-canonical interactions with the catalytic domain. Additionally it is essential in maintaining the structural integrity of Xrn1, since partial truncation of this domain in yeast Xrn1 yields an inactive protein. There is a long loop projecting from the SH3-like domain that contacts the PAZ/Tudor domain, occluding the functional surface that binds RNA or peptide motifs containing methylated arginines, respectively, in canonical PAZ and Tudor domain [1].
This family includes distant homologs of mitochondrial carrier proteins (MCs, also known in mammals as solute carrier family 25, SLC25). Sequence analysis suggest that it is likely that Lpg1137 forms a standard MC structure with a pseudo-threefold symmetry with six transmembrane helices. Furthermore, sequence logos of the repeats in homologues of Lpg1137, compared to sequence logo of the eukaryotic mitochondrial carriers support the structural similarity by highlighting the conservation of structurally important Pro and Gly residues (e.g., Pro at positions 15 and 239 in the logos or the YxG motif at positions 45-47 [1]. It was previously thought that members of this family are serine proteases that target the mitochondria-associated ER membrane (MAM) and degrades STX17 (syntaxin 17), a SNARE implicated in macroautophagy/autophagy as well as mitochondria dynamics and membrane trafficking in fed cells [2,3].
This family represents the N-terminal region of the eukaryotic epoxide hydrolase protein. Epoxide hydrolases (EC:3.3.2.3) comprise a group of functionally related enzymes that catalyse the addition of water to oxirane compounds (epoxides), thereby usually generating vicinal trans-diols. EHs have been found in all types of living organisms, including mammals, invertebrates, plants, fungi and bacteria. In animals, the major interest in EH is directed towards their detoxification capacity for epoxides since they are important safeguards against the cytotoxic and genotoxic potential of oxirane derivatives that are often reactive electrophiles because of the high tension of the three-membered ring system and the strong polarization of the C--O bonds. This is of significant relevance because epoxides are frequent intermediary metabolites which arise during the biotransformation of foreign compounds [1]. This family is often found in conjunction with Pfam:PF00561.
This domain is comprised of the iron-sulphur cluster and Rieske subunit found in the large subunit of arsenite oxidase. Arsenite oxidase is a 100 kDa molybdenum- and iron-sulfur-containing protein located on the outer surface of the inner membrane of Gram-negative organisms. The large subunit of arsenite oxidase is similar to other members of the dimethylsulfoxide (DMSO) reductase family of molybdenum enzymes. The large subunit of arsenite oxidase is divided into four domains, with domain I binding the [3Fe-4S] cluster . Domain I, consists of three antiparallel beta sheets and six helices. The [3Fe-4S] cluster is coordinated by the motif Cys21-X2-Cys24-X3-Cys28 near the interface with domains III and IV. A large, flattened funnel-like cavity bounded by domains I, II, and III leads to the molybdenum center Pfam:PF00384 located near the center of the molecule [1].
The REP domain of Mind bomb which serves as the substrate recognition domain for a second, membrane-distal epitope of the Notch ligand (C-box). Although the first Mib repeat of REP may play a dominant role in ligand binding, the two repeats appear to cooperate in the engagement of the Jag1 tail. Mind bomb (Mib) proteins are large, multi-domain E3 ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. The structure and functional analysis, show that Mib1 contains two independent substrate recognition domains that engage two distinct epitopes from the cytoplasmic tail of the ligand Jagged1, one in the intracellular membrane proximal region and the other near the C terminus. REP domains have a five-stranded anti-parallel twisted beta sheet topology similar to that of SH3 domains [1].
The family of bacterial Anabaena sensory rhodopsin transducers are likely to bind sugars or related metabolites. The entire protein is comprised of a single globular domain with an eight-stranded beta-sandwich fold. There are a few characteristics which define this beta-sandwich fold as being distinct from other so-named folds, and these are: 1) a well conserved tryptophan, usually following a polar residue, present at the start of the first strand; this tryptophan appears to be central to a hydrophobic interaction required to hold the two beta-sheets of the sandwich together, and 2) a nearly absolutely conserved asparagine located at the end of the second beta-strand, that hydrogen bonds with the backbone carbonyls of the residues 2 and 4 positions downstream from it, thereby stabilising the characteristic tight turn between strands 2 and 3 of the structure.
The RegB endoribonuclease encoded by bacteriophage T4 is a unique sequence-specific nuclease that cleaves in the middle of GGAG or, in a few cases, GGAU tetranucleotides, preferentially those found in the Shine-Dalgarno regions of early phage mRNAs. Phage RB49 in addition to RegB utilises Escherichia coli endoribonuclease E for the degradation of its transcripts for gene regB. The deduced primary structure of RegB proteins of 32 phages studied is almost identical to that of T4, while the sequences of RegB encoded by phages RB69, TuIa and RB49 show substantial divergence from their T4 counterpart. Rebuilding from the PDB:2hx6 structure, this family does not fall into the Lysozyme-like family, but rather is a new member of the RelE/YoeB structural and functional family of ribonucleases specialising in mRNA inactivation within the ribosome [2].
This is the conserved middle region of a family of proteins referred to as cactins. The region contains two of three predicted coiled-coil domains. Most members of this family have a CactinC_cactus Pfam:PF09732 domain at the C-terminal end. Upstream of Mid_cactin in Drosophila members are a serine-rich region, some non-typical RD motifs and three predicted bipartite nuclear localisation signals, none of which are well-conserved. Cactin associates with IkappaB-cactus as one of the intracellular members of the Rel (NF-kappaB) pathway which is conserved in invertebrates and vertebrates. In mammals, this pathway controls the activities of the immune and inflammatory response genes as well as viral genes, and is critical for cell growth and survival. In Drosophila, the Rel pathway functions in the innate cellular and humoral immune response, in muscle development, and in the establishment of dorsal-ventral polarity in the early embryo [1].
The central intermediate formed during mitotic and meiotic recombination is a four stranded DNA structure, also known as the Holliday junction (HJ), and its efficient resolution is essential for proper segregation of chromosomes. Resolution of HJs is mediated by a diverse group of DNA structure specific endonucleases known as Holliday junction resolvases (HJR) [1]. This entry is specific for RuvX also known as YqgF a family of nucleases which resolves the Holliday junction intermediates in genetic recombination[2-3]. Studies carried out in M. tuberculosis, have shown that YqgF/RuvX is a genuine HJR analogous to RuvC from E. coli. Furthermore, a single cysteine present in M. tuberculosis RuvX was found to be required for disulfide-bond mediated intermolecular dimerization and HJ resolution activity, suggesting that M. tuberculosis RuvX has adapted its YqgF protein to function like a typical RuvC family HJR [1].
Sporulation initiation phospho-transferase B or SpoOB is part of a phospho-relay that initiates sporulation in Bacillus subtilis. Spo0B is a two-domain protein consisting of an N-terminal alpha-helical hairpin domain and a C-terminal alpha/beta domain. Two subunits of Spo0B dimerise by a parallel association of helical hairpins to form a novel four-helix bundle from which the active histidine - involved in the auto-phosphorylation - protrudes. In the phospho-relay, the signal-receptor histidine kinases are dephosphorylated by a common response regulator, Spo0F. Spo0B then takes phosphorylated Spo0F as substrate thereby mediating the transfer of a phosphoryl group to Spo0A, the ultimate transcription factor. The exact function of this alpha-helical domain is not known; it does not always occur just as the N-terminal domain of SPOB_ab, Pfam:PF14682. SCOP describes this domain as a histidine kinase-like fold lacking the kinase ATP-binding site.
This family of peptidases contains a zinc metallopeptidase motif (HEXXHX(8,28)E) and possesses mucinase activity [1]. It includes the viral enhancins as well as enhancin-like peptidases from bacterial species. Enhancins are a class of metalloproteases found in some baculoviruses that enhance viral infection by degrading the peritrophic membrane (PM) of the insect midgut [1,2]. Bacterial enhancins are found to be cytotoxic when compared to viral enhancin, however, suggesting that the bacterial enhancins do not enhance infection in the same way as viral enhancin. Bacterial enhancins may have evolved a distinct biochemical function [2]. These bacterial domains are peptidases targetting host glycoproteins and thus probably play an important role in successful colonisation of both vertebrate mucosal surfaces and the invertebrate digestive tract by both mutualistic and pathogenic microbes [3]. This family has been augmented by a merge with the sequences in the Enhancin Pfam family.
Intimin and its translocated intimin receptor (Tir) are bacterial proteins that mediate adhesion between mammalian cells and attaching and effacing (A/E) pathogens. A unique and essential feature of A/E bacterial pathogens is the formation of actin-rich pedestals beneath the intimately adherent bacteria and localised destruction of the intestinal brush border. The bacterial outer membrane adhesin, intimin, is necessary for the production of the A/E lesion and diarrhoea. The A/E bacteria translocate their own receptor for intimin, Tir, into the membrane of mammalian cells using the type III secretion system. The translocated Tir triggers additional host signalling events and actin nucleation, which are essential for lesion formation [1]. This family represents the Tir intimin-binding domain (Tir IBD) which is needed to bind intimin and support the predicted topology for Tir, with both N- and C-terminal regions in the mammalian cell cytosol [2].
The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related proteins such as Smads. This domain is separated from the MH2 domain by a non-conserved linker region. The crystal structure of the MH1 domain shows that a highly conserved 11 residue beta hairpin is used to bind the DNA consensus sequence GNCN in the major groove, shown to be vital for the transcriptional activation of target genes. Not all examples of MH1 can bind to DNA however. Smad2 cannot bind DNA and has a large insertion within the hairpin that presumably abolishes DNA binding. A basic helix (H2) in MH1 with the nuclear localisation signal KKLKK has been shown to be essential for Smad3 nuclear import. Smads also use the MH1 domain to interact with transcription factors such as Jun, TFE3, Sp1, and Runx [1,3].
This is a family of unknown function. Family members are found in Bacteria and Eukaryotes. In algae, this family is found on the N-terminal of diphthamide synthase family Pfam:PF01902 and is predicted to be a membrane transporter belonging to The ATP-binding Cassette (ABC) family [1]. In nematoda, it is found on the N-terminal side of ribosomal protein family L14 Pfam:PF00238. It is also found on the N-terminal of Cob(I)alamin adenosyltransferase Pfam:PF01923 in other eukaryotes. Family members found in homo sapiens such as Swiss:Q5VUE5, have been shown to be highly expressed in 15 high-grade neuroendocrine tumor cell lines and YAP1-positive small-cell lung cancer cell lines [2] as well as being up-regulated in two human Multiple Myloma cell lines in response to selective nuclear export inhibitor KPT-276 [3]. The HMM profile of this family reveals 4 highly conserved cysteines.
GramPos_pilinD1 is the first subunit domain of Gram-positive pilins from Strep.pneumoniae. There are three major pilin subunits that form the polymeric backbone of the pilin from S. pneumoniae, constructed of three Ig-like, CnaB, domains along with a crucial N-terminal domain, D1. The three IG-like domains are stabilised by internal Lys-Asn isopeptide bonds, but this N-terminal domain makes few contact with the rest of the molecule due to the different orientation of its G beta-strand. Strand G of D1 also carries the YPKN motif that provides the essential Lys residue for the sortase-mediated intermolecular linkages along the pilus shaft. Gram-positive pili are formed from a single chain of covalently linked subunit proteins (pilins), usually comprising an adhesin at the distal tip, a major pilin that forms the polymer shaft and a minor pilin that mediates cell wall anchoring at the base [1].
In metazoans, Plk4 kinases control daughter centriole assembly. Plk4 homologs have an N-terminal kinase domain, a C-terminal polo box, and a central domain termed the 'cryptic polo box' (CPB) that has been shown to dimerize, to be sufficient for centriole localization and to be required for Plk4 to promote centriole assembly. Probable serine/threonine-protein kinase zyg-1 (EC:2.7.11.1) (ZYG-1) is a Plk4 homlog found in C. elegans. Crystal structure for the CPB of C. elegans ZYG-1, reveals that it forms a Z-shaped dimer containing an intermolecular beta-sheet with an extended basic surface patch. Electrostatic interactions between the basic patch on the ZYG-1 CPB dimer and the SPD-2 acidic region dock ZYG-1 onto centrioles to promote new centriole assembly. ZYG-1 CPB contains two tandem polo boxes (PB1 and PB2), each containing a six-stranded beta-sheet with an alpha-helix packed against one side [1].
In metazoans, Plk4 kinases control daughter centriole assembly. Plk4 homologs have an N-terminal kinase domain, a C-terminal polo box, and a central domain termed the 'cryptic polo box' (CPB) that has been shown to dimerize, to be sufficient for centriole localization and to be required for Plk4 to promote centriole assembly. Probable serine/threonine-protein kinase zyg-1 (EC:2.7.11.1) (ZYG-1) is a Plk4 homlog found in C. elegans. Crystal structure for the CPB of C. elegans ZYG-1, reveals that it forms a Z-shaped dimer containing an intermolecular beta-sheet with an extended basic surface patch. Electrostatic interactions between the basic patch on the ZYG-1 CPB dimer and the SPD-2 acidic region dock ZYG-1 onto centrioles to promote new centriole assembly. ZYG-1 CPB contains two tandem polo boxes (PB1 and PB2), each containing a six-stranded beta-sheet with an alpha-helix packed against one side [1]. This entry represents PB2.
The bacterial flagellar motor is a rotary motor complex composed of various proteins. MotX and MotY are essential for the Na+-driven flagellar motor motility of Vibrio, Shewanella and Aeromonas species. MotY is main component for T-ring formation and absence of MotY completely disrupt the T-ring formation [1]. This is the N-terminal domain of MotY which is shown to be essential for motility and responsible for the interaction with both MotX and the basal body. Functional analysis suggests that MotY-N connects the basal body to MotX and that the PomA/PomB complex associates with MotX to form the functional stator complex around the rotor. MotY-N alone does not associate strongly with the basal body, but the partial T-ring structure made of the MotY-N/MotX complex is sufficient to allow at least a few PomA/PomB stator complexes to be incorporated into the motor [2].
Iteration of the HHE family ([2]) found it to be related to Hemerythrin. It also demonstrated that what has been described as a single domain ([1]) in fact consists of two cation binding domains. Members of this family occur all across nature and are involved in a variety of processes. For instance, in Nereis diversicolor Swiss:P80255 binds Cadmium so as to protect the organism from toxicity ([3]). However Hemerythrin is classically described as Oxygen-binding through two attached Fe2+ ions. And the bacterial Swiss:Q7WX96 is a regulator of response to NO, which suggests yet another set-up for its metal ligands ([4]). In Staphylococcus aureus P72360 has been noted to be important when the organism switches to living in environments with low oxygen concentrations ([4]); perhaps this protein acts as an oxygen store or scavenger. This domain can bind oxygen (Matilla et.al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043)
Members of this family are found in both fungi, bacteria and wood-eating arthropods. The domain is found at the N-terminus of rhamnogalacturonase B, a member of the polysaccharide lyase family 4. The domain adopts a structure consisting of a beta super-sandwich, with eighteen strands in two beta-sheets [1]. The three domains of the whole protein rhamnogalacturonan lyase (RGL4), are involved in the degradation of rhamnogalacturonan-I, RG-I, an important pectic plant cell-wall polysaccharide. The active-site residues are a lysine at position 169 in UniProtKB:Q00019 and a histidine at 229, Lys169 is likely to be a proton abstractor, His229 a proton donor in the mechanism. The substrate is a disaccharide, and RGL4, in contrast to other rhamnogalacturonan hydrolases, cleaves the alpha-1,4 linkages of RG-I between Rha and GalUA through a beta-elimination resulting in a double bond in the nonreducing GalUA residue, and is thus classified as a polysaccharide lyase (PL) [2].
This domain is found in human cytoplasmic dynein-2 proteins. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Structural analysis reveal that the motor's ring consists of six AAA+ domains (ATPases associated with various cellular activities (AAA1-AAA6). This is the fifth AAA+ domain subdomain AAA5S. Structural analysis reveal that it is the coiled-coil buttress interface. The relative movement of AAA5S together with the stalk (AAA4S), is coupled to rearrangements in the AAA+ ring. Closure of the AAA1 site and the rigid body movement of AAA2-AAA4 force the AAA4/AAA5 interface to close and the AAA6L subdomain to rotate towards the ring centre. The AAA5S subdomain rotates as a unit together with AAA6L, and this movement pulls the buttress relative to the stalk [1].
STN1 is a component of the CST complex, a complex that binds to single-stranded DNA and is required for protecting telomeres from DNA degradation. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity on their own. In addition to telomere protection, the CST complex probably has a more general role in DNA metabolism at non-telomeric sites. This entry represents the C-terminal region of Stn1 which has two winged helix-turn-helix (wHTH) motifs, wHTH1 and wHTH2 [2,4]. wHTH1 is structurally similar to that in RPA32 with a large insertion between helices alpha2 and alpha3, unique to Stn1, that may allow interaction with a different set of proteins that function at telomeres such as Ctc1 [4]. wHTH2 is most similar to the DNA-binding wHTH motifs of the pur operon repressor and RepE replication initiator, but it does not bind double-stranded DNA [5].
Members of this family are involved in cobalamin synthesis. The gene encoded by Swiss:P72862 has been designated cbiH but in fact represents a fusion between cbiH and cbiG. As other multi-functional proteins involved in cobalamin biosynthesis catalyse adjacent steps in the pathway, including CysG, CobL (CbiET), CobIJ and CobA-HemD, it is therefore possible that CbiG catalyses a reaction step adjacent to CbiH. In the anaerobic pathway such a step could be the formation of a gamma lactone, which is thought to help to mediate the anaerobic ring contraction process [1]. Within the cobalamin synthesis pathway CbiG catalyses the both the opening of the lactone ring and the extrusion of the two-carbon fragment of cobalt-precorrin-5A from C-20 and its associated methyl group (deacylation) to give cobalt-precorrin-5B [2]. This family is the C-terminal region, and the mid- and N-termival parts are conserved independently in other families.
These are metalloenzymes that function as the ubiquitin isopeptidase/ deubiquitinase in the ubiquitin-based signaling and protein turnover pathways in eukaryotes [1]. Prokaryotic JAB domains are predicted to have a similar role in their cognates of the ubiquitin modification pathway [2]. The domain is widely found in bacteria, archaea and phages where they are present in several gene contexts in addition to those that correspond to the prokaryotic cognates of the eukaryotic Ub pathway. Other contexts in which JAB domains are present include gene neighbor associations with ubiquitin fold domains in cysteine and siderophore biosynthesis, and phage tail morphogenesis, where they are shown or predicted to process the associated ubiquitin [2,3]. A distinct family, the RadC-like JAB domains are widespread in bacteria and are predicted to function as nucleases [4]. In halophilic archaea the JAB domain shows strong gene-neighborhood associations with a nucleotidyltransferase suggesting a role in nucleotide metabolism [4].
LC3 Interacting Regions (LIRs), also known as ATG8-interacting motifs (AIMs), are short-linear motifs (SLiMs) of autophagy receptors and adaptor proteins that facilitates the selective recruitment of autophagy substrates to the autophagosome. LIRs are characterised by degenerated sequences with a four-residue core central sequence involved in ATG8-binding, with the W/Y/FxxL/I/V pattern. Based on the aromatic amino acid in position 1 they can be classified into W-type, Y-type and F-type [1]. This entry includes three conserved LIR motifs of CADHs, which two are Y-type (YDxL/I) and one F-type (FKKL), while a fourth LIR (YGGV) is only present in CADH6 members [2]. Cadherins (CADH) have a crucial role in epithelial-to-mesenchymal transition (EMT), involved in migration properties of tumour cells. CADH6 is an EMT marker in thyroid cancer that interacts with the ATG8 family members GABARAP, BNIP3 and BNIP3L restraining autophagy through LIR domains, a common feature among many cadherin family members [2].
Glutaredoxins are a multifunctional family of glutathione-dependent disulphide oxidoreductases. Unlike other glutaredoxins, glutaredoxin 2 (Grx2) cannot reduce ribonucleotide reductase. Grx2 has significantly higher catalytic activity in the reduction of mixed disulphides with glutathione (GSH) compared with other glutaredoxins. The active site residues (Cys9-Pro10-Tyr11-Cys12, in Escherichia coli Grx2, Swiss:P39811), which are found at the interface between the N- and C-terminal domains are identical to other glutaredoxins, but there is no other similarity between glutaredoxin 2 and other glutaredoxins. Grx2 is structurally similar to glutathione-S-transferases (GST), but there is no obvious sequence similarity. The inter-domain contacts are mainly hydrophobic, suggesting that the two domains are unlikely to be stable on their own. Both domains are needed for correct folding and activity of Grx2. It is thought that the primary function of Grx2 is to catalyse reversible glutathionylation of proteins with GSH in cellular redox regulation including the response to oxidative stress.
Bacteriophages recognize and bind to their hosts with the help of receptor-binding proteins (RBPs) that emanate from the phage particle in the form of fibers or tailspikes. RBPs of podovirus G7C tailspikes gp63.1 and gp66 are essential for infection of its natural host bacterium E. coli 4s. Gp63.1 and gp66 form a stable complex, in which the N-terminal part of gp66 serves as an attachment site for gp63.1 and anchors the gp63.1-gp66 complex to the G7C tail. The two N-terminal domains show 70% sequence identity to the N-terminal region of the CBA120 phage tailspike 1 (orf210, TSP1) [1]. The N-terminal domain of TSP1 is the virion head binding domain that interfaces with the phage baseplate. The N-terminal domain can be further divided into two subdomains, each beginning with a alpha-helix followed by an anti-parallel beta-sandwich. Subdomain two folds similarly to the chitin binding domain of Chitinase from Bacillus circulans [2].
Intimin and its translocated intimin receptor (Tir) are bacterial proteins that mediate adhesion between mammalian cells and attaching and effacing (A/E) pathogens. A unique and essential feature of A/E bacterial pathogens is the formation of actin-rich pedestals beneath the intimately adherent bacteria and localised destruction of the intestinal brush border. The bacterial outer membrane adhesin, intimin, is necessary for the production of the A/E lesion and diarrhoea. The A/E bacteria translocate their own receptor for intimin, Tir, into the membrane of mammalian cells using the type III secretion system. The translocated Tir triggers additional host signalling events and actin nucleation, which are essential for lesion formation [1]. This family represents the Tir C-terminal domain which has been reported to bind uninfected host cells and beta-1 integrins although the role of intimin binding to integrins is unclear. This intimin C-terminal domain has also been shown to be sufficient for Tir recognition [2].
cEGF, or complement Clr-like EGF, domains have six conserved cysteine residues disulfide-bonded into the characteristic pattern 'ababcc'. They are found in blood coagulation proteins such as fibrillin, Clr and Cls, thrombomodulin, and the LDL receptor. The core fold of the EGF domain consists of two small beta-hairpins packed against each other. Two major structural variants have been identified based on the structural context of the C-terminal cysteine residue of disulfide 'c' in the C-terminal hairpin: hEGFs and cEGFs. In cEGFs the C-terminal thiol resides on the C-terminal beta-sheet, resulting in long loop-lengths between the cysteine residues of disulfide 'c', typically C[10+]XC. These longer loop-lengths may have arisen by selective cysteine loss from a four-disulfide EGF template such as laminin or integrin. Tandem cEGF domains have five linking residues between terminal cysteines of adjacent domains. cEGF domains may or may not bind calcium in the linker region. cEGF domains with the consensus motif CXN4X[F,Y]XCXC are hydroxylated exclusively on the asparagine residue.
The small ubiquitin-related modifier SUMO-1 is a Ub/Ubl family member, and although SUMO-1 shares structural similarity to Ub, SUMO's cellular functions remain distinct insomuch as SUMO modification alters protein function through changes in activity, cellular localisation, or by protecting substrates from ubiquitination [1]. Rad60 family members contain functionally enigmatic, integral SUMO-like domains (SLDs). Despite their divergence from SUMO, each Rad60 SLD interacts with a subset of SUMO pathway enzymes: SLD2 specifically binds the SUMO E2 conjugating enzyme (Ubc9)), whereas SLD1 binds the SUMO E1 (Fub2, also called Uba2) activating and E3 (Pli1, also called Siz1 and Siz2) specificity enzymes. Structural analysis of PDB:2uyz reveals a mechanistic basis for the near-synonymous roles of Rad60 and SUMO in survival of genotoxic stress and suggest unprecedented DNA-damage-response functions for SLDs in regulating SUMOylation [2]. The Rad60 branch of this family is also known as RENi (Rad60-Esc2-Nip45), and biologically it should be two distinct families SUMO and RENi (Rad60-Esc2-Nip45).
The misato protein contains three distinct, conserved domains, segments I, II and III. Segments I and III are common to Tubulins Pfam:PF00091, but segment II aligns with myosin heavy chain sequences from D. melanogaster (PIR C35815), rabbit (SP P04460), and human (PIR S12458). 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 is homologous to 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 alpha-helical coiled-coils [1]. This myosin-like homology may be due only to the fact that both myosin and Misato carry coiled-coils, which appear similar but are not necessarily homologous (Wood V, personal communication).
Mediator is a large complex of up to 33 proteins that is conserved from plants to fungi to humans - the number and representation of individual subunits varying with species {1-2]. It is arranged into four different sections, a core, a head, a tail and a kinase-activity part, and the number of subunits within each of these is what varies with species. Overall, Mediator regulates the transcriptional activity of RNA polymerase II but it would appear that each of the four different sections has a slightly different function [3]. Mediator exists in two major forms in human cells: a smaller form that interacts strongly with pol II and activates transcription, and a large form that does not interact strongly with pol II and does not directly activate transcription. The ubiquitous expression of Med27 mRNA suggests a universal requirement for Med27 in transcriptional initiation. Loss of Crsp34/Med27 decreases amacrine cell number, but increases the number of rod photoreceptor cells [4].
This domain family is found in bacteria, and is approximately 40 amino acids in length. The proteins in this family are members of the acetyltransferases of the GNAT family. Family members such as PanZ has been shown to be involved in the biosynthesis of Coenzyme A (CoA). CoA is a ubiquitous and essential cofactor, synthesized from the precursor pantothenate. In all organisms, the final step in pantothenate biosynthesis relies on the presence of beta-alanine, which comes from different sources in bacteria, yeast, and plants. In bacteria, beta-alanine is derived by the action of alpha-decarboxylase (ADC) enzyme. PanZ promotes the activation of the zymogen, PanD, to form aspartate alpha-decarboxylase (ADC) in a CoA-dependent manner. Thereby, playing an essential role in the biosynthetic pathway to pantothenate and the regulation of CoA biosynthesis. Structure and function studies show that direct interaction of PanD with the PanZ Arg43-Leu46 loop promotes PanD to adopt a reactive conformation, which leads to activation [1].
Interactions with ankyrin-G are crucial to the localisation of voltage-gated sodium channels (VGSCs) at the axon initial segment and for neurons to initiate action potentials. This conserved 9-amino acid motif ((V/A)P(I/L)AXXE(S/D)D) is required for ankyrin-G binding and functions to localise sodium channels to a variety of 'excitable' membrane domains both inside and outside of the nervous system [1]. This motif has also been identified in the potassium channel 6TM proteins KCNQ2 and KCNQ3 [2], that correspond to the M channels that exert a crucial influence over neuronal excitability. KCNQ2/KCNQ3 channels are preferentially localised to the surface of axons both at the axonal initial segment and more distally, and this axonal initial segment targeting of surface KCNQ channels is mediated by these ankyrin-G binding motifs of KCNQ2 and KCNQ3 [3]. KCNQ3 is a major determinant of M channel localisation to the AIS, rather than KCNQ2 [4]. Phylogenetic analysis reveals that anchor motifs evolved sequentially in chordates (NaV channel) and jawed vertebrates (KCNQ2/3) [5].
C-terminal jelly roll/Ig-like domain (C-JID) was defined in cryogenic electron microscopy (cryoEM) structures of plant intracellular immune receptors containing Toll/interleukin-1 receptor (TIR, PF01582), nucleotide-binding (NB-ARC, PF00931) and leucine-rich repeat (LRR) domains (TIR-NLRs) [1,2]. Structurally, the C-JID core is represented by a beta-sandwich made up of 8 to 9 beta-strands. C-JID matches the so-called post LRR domain originally detected via a set of MEME motifs [3]. The domain showed a strong distribution bias towards TIR-NLRs of dicotyledonous plant species despite broader taxonomic distribution of TIR-NLR in plant groups [1-3]. Structure-function analyses of cryoEM structures suggest that C-JID domains play a role in substrate-recognition, such as binding to effector proteins from pathogens, and thus are involved in the initiation of signaling by TIR-NLR receptors [1, 2]. Presence of C-JID (or post-LRR) and its importance for the function of Arabidopsis TIR-NLR RPS4 that partners with RRS1 for effector recognition suggest that C-JID has additional functions [4-6].
