SII-SWORD/CoKE huggingface dataset:
Zinc finger, CHY-type superfamily (Znf_CHY_sf)
Type: Homologous_superfamily

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

Pirh2 is an eukaryotic ubiquitin protein ligase, which has been shown to promote p53 degradation in mammals. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of MDM2. Like MDM2, Pirh2 is thought to participate in an autoregulatory feedback loop that controls p53 function. Pirh2 proteins contain three distinct zinc fingers, the CHY-type, the CTCHY-type which is C-terminal to the CHY-type zinc finger and a RING finger. The CHY-type zinc finger has no currently known function .

As well as Pirh2, the CHY-type zinc finger is also found in the following proteins:

Yeast helper of Tim protein 13. Hot13 may have a role in the assembly and recycling of the small Tims, a complex of the mitochondrial intermembrane space that participates in the TIM22 import pathway for assembly of the inner membrane

Several plant hypothetical proteins that also contain haemerythrin cation binding domains

Several protozoan hypothetical proteins that also contain a Myb domain

The solution structure of this zinc finger has been solved and binds three zinc atoms as shown in the following schematic representation:

++---------+-----+
|| | |
CXHYxxxxxxxxxCCxxxxxCxxCHxxxxxHxxxxxxxxxxxCxxCxxxxxxxxxCxxC
| | | | | | | |
+-+-----------------+--+ +--+---------+--+

'C': conserved cysteine involved in the binding of one zinc atom.
'H': conserved histidine involved in the binding of one zinc atom.
Zinc finger, CTCHY-type superfamily (Znf_CTCHY_sf)
Type: Homologous_superfamily

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

Pirh2 is an eukaryotic ubiquitin protein ligase, which has been shown to promote p53 degradation in mammals. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of MDM2. Like MDM2, Pirh2 is thought to participate in an autoregulatory feedback loop that controls p53 function. Pirh2 proteins contain three distinct zinc fingers, the CHY-type, the CTCHY-type which is C-terminal to the CHY-type zinc finger and a RING finger. The CHY-type zinc finger has no known functions but the region encompassing the CTCHY-type zinc finger is required for binding to p53 in mammals .

The CTCHY-type zinc finger has so far only been found in Pirh2 proteins. It binds 3 zinc atoms as shown in the following schematic representation:

The CTCHY-type zinc finger:

+--+------------+------+
| | | |
CxxCxxxxxxxxxxHCxxCxxCxxxxxxxxxHCxxCxxCxxxxxxxxHxC
| | | | | | | |
+--+----------+------+ +--+-----------+-+

'C': conserved cysteine involved in the binding of one zinc atom.
'H': conserved histidine involved in the binding of one zinc atom.
Granulin superfamily (Granulin_sf)
Type: Homologous_superfamily

Metazoan granulins are a family of cysteine-rich peptides of about 6 Kd which may have multiple biological activity. A precursor protein (known as acrogranin) potentially encodes seven different forms of granulin (grnA to grnG) which are probably released by post-translational proteolytic processing. Granulins are evolutionary related to PMP-D1, a peptide extracted from the pars intercerebralis of migratory locusts . A schematic representation of the structure of a granulin is shown below:

xxxCxxxxxCxxxxxCCxxxxxxxxCCxxxxxxCCxxxxxCCxxxxxCxxxxxxCx

'C': conserved cysteine probably involved in a disulphide bond.

In plants a granulin domain is often associated with the C terminus of cysteine proteases belong to the MEROPS peptidase family C1, subfamily C1A (papain).
ARFGAP/RecO-like zinc finger (ARFGAP/RecO)
Type: Homologous_superfamily

The ARFGAP domain was first identified in the cell cycle control GTPase activating protein (GAP) GCS1 . GCS1 is important for the inactivation of the ADP ribosylation factor ARF a member of the Ras superfamily of GTP-binding proteins. GTP-bound form of ARF is essential for the maintenance of normal Golgi morphology, it participates in recruitment of coat proteins which are required for budding and fission of membranes. Before the fusion with an acceptor compartment the membrane must be uncoated. This step required the hydrolysis of GTP associated to ARF, a process dependent on the ARFGAP domain of GCS1 .

The ARFGAP domain contains a characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-Cys-x2-Cys) which displays some similarity to the C4-type GATA zinc finger. The ARFGAP domain display no obvious similarity to other GAP proteins. However a C4-type zinc finger is also found in the ARD1 GAP domain .

RecO is a DNA repair protein involved in damage avoidance-tolerance pathway(s) .
Photosystem I PsaM, reaction centre superfamily (PSI_PsaM_sf)
Type: Homologous_superfamily

This entry represents a domain found in the PsaM protein, which is subunit XII of the photosystem I reaction centre. PsaM forms part of the photosystem I complex and its binding is stabilised by PsaI . This protein is found in both the Cyanobacteria and the chloroplasts of plants, but is absent from non-oxygenic photosynthetic bacteria such as Rhodobacter sphaeroides. Species that contain photosystem I also contain photosystem II, which splits water and releases molecular oxygen.
F-actin-capping protein subunit alpha/beta (CapZ_alpha/beta)
Type: Homologous_superfamily

The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha (

) and beta (

). Neither of the subunits shows sequence similarity to other filament-capping proteins .

This entry represents the alpha and beta subunits of the F-actin-capping protein.
The alpha subunit (CAPZA) is a protein of about 268 to 286 amino acid residues and the beta subunit (CAPZB) is about 280 amino acid residues.
Their sequences are well conserved in eukaryotic species . In Drosophila mutations in the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration . In humans CAPZA and CAPZB are part of the WASH complex that controls the fission of endosomes .
SUF system FeS cluster assembly, SufBD superfamily (SUF_FeS_clus_asmbl_SufBD_sf)
Type: Homologous_superfamily

Iron-sulphur (FeS) clusters are important cofactors for numerous proteins involved in electron transfer, in redox and non-redox catalysis, in gene regulation, and as sensors of oxygen and iron. These functions depend on the various FeS cluster prosthetic groups, the most common being [2Fe-2S] and [4Fe-4S] . FeS cluster assembly is a complex process involving the mobilisation of Fe and S atoms from storage sources, their assembly into [Fe-S] form, their transport to specific cellular locations, and their transfer to recipient apoproteins. So far in bacteria, three FeS assembly machineries have been identified that are capable of synthesising all types of [Fe-S] clusters: ISC (iron-sulphur cluster), SUF (sulphur assimilation), and NIF (nitrogen fixation) systems.

The ISC system is conserved in eubacteria and eukaryotes (mitochondria) and has broad specificity, targeting general FeS proteins . It is encoded by the isc operon (iscRSUA-hscBA-fdx-iscX). IscS is a cysteine desulphurase, which obtains S from cysteine (converting it to alanine) and serves as a S donor for FeS cluster assembly. IscU and IscA act as scaffolds to accept S and Fe atoms, assembling clusters and transferring them to recipient apoproteins. HscA is a molecular chaperone and HscB is a co-chaperone. Fdx is a [2Fe-2S]-type ferredoxin. IscR is a transcription factor that regulates expression of the isc operon. IscX (also known as YfhJ) appears to interact with IscS and may function as an Fe donor during cluster assembly .

The SUF system is an alternative pathway to the ISC system that operates under iron starvation and oxidative stress. It is found in eubacteria, archaea and eukaryotes (plastids). The SUF system is encoded by the suf operon (sufABCDSE), and the six encoded proteins are arranged into two complexes (SufSE and SufBCD) and one protein (SufA). SufS is a pyridoxal-phosphate (PLP) protein displaying cysteine desulphurase activity. SufE acts as a scaffold protein that accepts S from SufS and donates it to SufA . SufC is an ATPase with an unorthodox ATP-binding cassette (ABC)-like component. SufA is homologous to IscA , acting as a scaffold protein in which Fe and S atoms are assembled into [FeS] cluster forms, which can then easily be transferred to apoprotein targets.

In the NIF system, NifS and NifU are required for the formation of metalloclusters of nitrogenase in Azotobacter vinelandii, and other organisms, as well as in the maturation of other FeS proteins. Nitrogenase catalyses the fixation of nitrogen. It contains a complex cluster, the FeMo cofactor, which contains molybdenum, Fe and S. NifS is a cysteine desulphurase. NifU binds one Fe atom at its N-terminal, assembling an FeS cluster that is transferred to nitrogenase apoproteins . Nif proteins involved in the formation of FeS clusters can also be found in organisms that do not fix nitrogen .
TM0693-like superfamily (TM0693-like_sf)
Type: Homologous_superfamily

This entry represents the hypothetical protein TM0693. Its structure consists of a helix-swapped dimer in which the two last helices of this fold form a single coiled-coil helix.
Elongator complex protein 2 (Elp2)
Type: Family

Elongator complex protein 2 (Elp2) is a component of the RNA polymerase II elongator complex, which is a major histone acetyltransferase component of the RNA polymerase II (RNAPII) holoenzyme. The eukaryotic elongator complex has been associated with many cellular activities, including transcriptional elongation , but its main function is tRNA modification . It is required for the formation of 5-methoxy-carbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) groups on uridine nucleosides present at the wobble position of many tRNAs .
Domain of unknown function DUF4139 (DUF4139)
Type: Domain

This domain is usually found at the C terminus of proteins.
Protein D-63 superfamily (D-63_sf)
Type: Homologous_superfamily

The structure of Sulfolobus spindle-shaped virus 1 (SSV1) protein D-63 reveals a helix-turn-helix motif that dimerises to form an antiparallel four-helix bundle. Its structure suggests that it may function as an adaptor protein in macromolecular assembly .
Galactose oxidase, central domain superfamily (Gal_Oxidase_central_sf)
Type: Homologous_superfamily

This entry represents a β-propeller domain found in galactose oxidase.

Galactose oxidase (

) is a monomeric enzyme that contains a single copper ion and catalyses the stereospecific oxidation of primary alcohols to their corresponding aldehyde . The protein contains an unusual covalent thioether bond between a tyrosine and a cysteine that forms during its maturation . Galactose oxidase is a three-domain protein: the N-terminal domain forms a jelly-roll sandwich, the central domain forms a seven 4-bladed β-propeller, and the C-terminal domain has an immunoglobulin-like fold.
ABC transporter, BtuC-like (ABC_BtuC-like)
Type: Homologous_superfamily

This entry represents a domain found in some ABC transporter permease proteins, such as BtuC (involved in vitamin B12 uptake) and metal-chelatin transporters . It consists of a multihelical, complex architecture with several transmembrane helices.

ABC transporter BtuCD consists of two ATP-binding cassettes (BtuD) and two membrane-spanning subunits (BtuC). The BtuC subunits provide 20 transmembrane helices grouped around a translocation pathway that is closed to the cytoplasm by a gate region. A prominent cytoplasmic loop of BtuC forms the contact region with the ATP-binding cassette .

This entry also includes FecC and FecD, which are components of the fec operon, a Periplasmic-Binding-Protein (PBP)-dependent transport system for ferric dicitrate in Escherichia coli . FecC and FecD exhibit homology to each other and are localized in the cytoplasmic membrane.
Alpha-lytic protease prodomain (Alpha-lytic_protease_prodomain)
Type: Homologous_superfamily

This entry represents the prodomain of alpha-lytic endopeptidase. Alpha-lytic endopeptidase is synthesised as a pro-enzyme where its pro region (Pro) acts as a foldase to stabilise the transition state for the folding reaction. Pro also functions as a potent folding catalyst when supplied as a separate polypeptide chain. In the absence of Pro, alpha-lytic endopeptidase folds only partially to a stable molten globule-like intermediate state. Addition of Pro to this intermediate leads to rapid formation of native alpha-lytic endopeptidase .
Staphostatin A/B (Staphostatin_A/B)
Type: Homologous_superfamily

Staphostatin A (SAV1910, SA1726) and B (SspC) are cysteine protease inhibitors belonging to MEROPS inhibitor families I57 and I58 (clan IK). They have a β-barrel topology that act as specific inhibitors of staphopains, the major secreted cysteine proteases of Staphylococcus aureus . These inhibitors compete with substrate for binding at the active site of the staphopain, acting to protect intracellular proteins against proteolytic damage by prematurely folded and activated staphopains . They are also involved in growth capacity, viability and bacterial morphology.
Probable ABC transporter arginine-binding protein ArtJ, PBP2 domain (ArtJ_PBP2)
Type: Domain

This entry represents the periplasmic binding domain type 2 (PBP2) found in the arginine-binding proteins from Chlamydiae trachomatis (CT-ArtJ) and pneumoniae (CPn-ArtJ) and closely related proteins. CT- and CPn-ArtJ are shown to have different immunogenic properties despite a high sequence similarity. The ArtJ proteins display the PBP2 fold organized in two α-β domains with arginine-binding region at their interface .
Cyclohexadienyl dehydratase PheC (PheC_PBP2)
Type: Domain

This entry represents the periplasmic binding protein type 2 (PBP2) domain found in cyclohexadienyl dehydratase PheC . Proteins containing this domain catalyze the decarboxylation of prephenate to phenylpyruvate in the alternative phenylalanine biosynthesis pathway in some proteobacteria and archaea . The PheC proteins belong to the PBP2 superfamily of periplasmic binding proteins that differ in size and ligand specificity, but have similar tertiary structures consisting of two globular subdomains connected by a flexible hinge. They have been shown to bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap . Since the PheC proteins are so similar to periplasmic binding proteins, (PBP), it is evolutionary plausible that several pre-existing PBP proteins might have been recruited to perform the enzymatic function.
TRIM37, MATH domain (TRIM37_MATH)
Type: Domain

This entry represents the MATH (meprin and TRAF homology) domain found in TRIM37, which is a member of the tripartite motif (RING, B-Box, and coiled-coil domains) family and has E3 ubiquitin ligase activity toward itself and histone H2A protein . TRIM37 localizes to peroxisomes . Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterised by dysmorphic features, pericardial constriction and hepatomegaly .
Perforin-1, C2 domain (Perforin-1_C2)
Type: Domain

Perforin-1 contains a single copy of a C2 domain in its C terminus and plays a role in lymphocyte-mediated cytotoxicity . Mutations in perforin-1 lead to familial hemophagocytic lymphohistiocytosis type 2, a rare, rapidly fatal, autosomal recessive immune disorder characterised by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines . The function of perforin-1 is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements, type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances, including phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this, including RIM isoforms and some splice variants of piccolo/aczonin and intersectin, which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
Toll-interacting protein, C2 domain (Tollip_C2)
Type: Domain

Tollip is a part of the Interleukin-1 receptor (IL-1R) signaling pathway. Tollip is proposed to link serine/threonine kinase IRAK to IL-1Rs as well as inhibiting phosphorylation of IRAK . The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates . There is a single C2 domain present in Tollip.

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements, type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances, including phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this, including RIM isoforms and some splice variants of piccolo/aczonin and intersectin, which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
Protein Unc-13, C2B domain (Unc-13_C2B)
Type: Domain

C. elegans Unc-13 is a phorbol ester/diacylglycerol-binding protein that plays a role in vesicle maturation during exocytosis . Unc-13 disruption causes diverse defects in the nervous system . Mammals contain three Unc-13 homologues: Unc-13 A, B and C (also known as Munc13-1/2/3) . Unc13 homologue C is cerebellum-specific and regulates cerebellar synaptic transmission . Homologues A and B are involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion . They are essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses .

Unc-13 and its homologues contain both C1 and C2 domains. There are at least two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. The central C2 domain (C2B) is part of a C1-C2 tandem that functions in part to inhibit calcium-triggered neurotransmitter release. The C1 domain of Munc13 binds diacylglycerol (DAG) and beta phorbol esters (beta-PEs), while the neighbouring C2 domain (C2B) binds calcium and anionic phospholipids with a preference for both PI(4)P and PI(4,5)P2 .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements, type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances, including phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this, including RIM isoforms and some splice variants of piccolo/aczonin and intersectin, which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .