SII-SWORD/CoKE huggingface dataset:
MHC class II, alpha/beta chain, N-terminal (MHC_II_a/b_N)
Type: Homologous_superfamily

Major Histocompatibility Complex (MHC) glycoproteins are heterodimeric cell surface receptors that function to present antigen peptide fragments to T cells responsible for cell-mediated immune responses. MHC molecules can be subdivided into two groups on the basis of structure and function: class I molecules present intracellular antigen peptide fragments (~10 amino acids) on the surface of the host cells to cytotoxic T cells; class II molecules present exogenously derived antigenic peptides (~15 amino acids) to helper T cells. MHC class I and II molecules are assembled and loaded with their peptide ligands via different mechanisms. However, both present peptide fragments rather than entire proteins to T cells, and are required to mount an immune response.

Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as bacteria. Proteins from the pathogen are degraded into peptide fragments within the APC, which sequesters these fragments into the endosome so they can bind to MHC class II proteins, before being transported to the cell surface. MHC class II receptors display antigens for recognition by helper T cells (stimulate development of B cell clones) and inflammatory T cells (cause the release of lymphokines that attract other cells to site of infection) .

MHC class II molecules are comprised of two membrane-spanning chains, alpha and beta, of similar size. Both chains consist of two globular domains (N-and C-terminal), and a transmembrane segment to anchor them to the membrane . A groove in the structure acts as the peptide-binding site.

This superfamily represents the N-terminal domain of both the alpha and beta chains, which share the same α-helical/β-sheet fold, where the α-helical and β-sheet regions are segregated.
Glutamine synthetase/guanido kinase, catalytic domain (Gln_synth/guanido_kin_cat_dom)
Type: Homologous_superfamily

The C-terminal catalytic domains of glutamine synthetase and the guanido kinase family (which includes creatine kinase and arginine kinase) share a common structural fold, namely a common core consisting of two β-α-β2-α repeats .

Glutamine synthetase (

) (GS) plays an essential role in the metabolism of nitrogen by catalysing the condensation of glutamate and ammonia to form glutamine. There seem to be three different classes of GS . Class I enzymes (GSI) are specific to prokaryotes, and are oligomers of 12 identical subunits; the activity of GSI-type enzyme is controlled by the adenylation of a tyrosine residue. Class II enzymes (GSII) are found in eukaryotes and in bacteria, and are oligomers of 8 identical subunits. Class III enzymes (GSIII) have been found in Bacteroides fragilis in Butyrivibrio fibrisolvens, and are oligomers of six identical subunits. While the three classes of GS's are clearly structurally related, the sequence similarities are not so extensive.

ATP:guanido phosphotransferases are a family of structurally and functionally related enzymes that reversibly catalyse the transfer of phosphate between ATP and various phosphogens. The enzymes belonging to this family include:

Glycocyamine kinase (

), which catalyses the transfer of phosphate from ATP to guanidoacetate.

Arginine kinase (

), which catalyses the transfer of phosphate from ATP to arginine.

Taurocyamine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to taurocyamine.

Lombricine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to lombricine.

Smc74, a cercaria-specific enzyme from Schistosoma mansoni .

Creatine kinase (

) (CK) , which plays an important role in energy metabolism of vertebrates.
Bacterial photosynthetic reaction centre, H-chain, C-terminal (Bac_photo_RC_H_C)
Type: Homologous_superfamily

This superfamily represents the barrel domain of the H subunit from the photosynthetic reaction centre (PRC). The H subunit has a single transmembrane helix and a large cytoplasmic domain . The core of the cytoplasmic domain contains the PRC-barrel.

The photosynthetic apparatus in non-oxygenic bacteria consists of light-harvesting (LH) protein-pigment complexes LH1 and LH2, which use carotenoid and bacteriochlorophyll as primary donors . LH1 acts as the energy collection hub, temporarily storing it before its transfer to the photosynthetic reaction centre (RC) . Electrons are transferred from the primary donor via an intermediate acceptor (bacteriopheophytin) to the primary acceptor (quinine Qa), and finally to the secondary acceptor (quinone Qb), resulting in the formation of ubiquinol QbH2. RC uses the excitation energy to shuffle electrons across the membrane, transferring them via ubiquinol to the cytochrome bc1 complex in order to establish a proton gradient across the membrane, which is used by ATP synthetase to form ATP .

The core complex is anchored in the cell membrane, consisting of one unit of RC surrounded by LH1; in some species there may be additional subunits . RC consists of three subunits: L (light), M (medium), and H (heavy). Subunits L and M provide the scaffolding for the chromophore, while subunit H contains a cytoplasmic domain . In Rhodopseudomonas viridis, there is also a non-membranous tetrahaem cytochrome (4Hcyt) subunit on the periplasmic surface.
Enoyl-CoA hydratase, C-terminal (Enoyl-CoA_hydra_C)
Type: Homologous_superfamily

This entry represents the C-terminal domain found in enoyl-CoA hydratase and related proteins. This domain has an α-helical structure, and may be involved in trimerisation.
DNA repair protein XRCC4-like, C-terminal (XRCC4-like_C)
Type: Homologous_superfamily

XRCC4 is essential for non-homologous DNA end joining (NHDJ) in eukaryotes, which is required for double-strand break repair, and V(D)J recombination in immunoglobulin and T-cell receptor genes. XRCC4 forms a complex with DNA ligase IV, and acts as a regulatory element required for the stability and activity of the ligase. XRCC4 forms an elongated dumb-bell-like tetramer consisting of a C-terminal stalk that interacts with DNA ligase IV and an N-terminal globular head. The C-terminal oligomerisation domain consists of oligomers of short identical helices that form parallel coiled-coils .

This superfamily also matches the C-terminal of the coiled-coil myosin heavy chain tail region. Muscle contraction is caused by sliding between the thick and thin filaments of the myofibril. Myosin is a major component of thick filaments and exists as a hexamer of 2 heavy chains , 2 alkali light chains, and 2 regulatory light chains. The heavy chain can be subdivided into the N-terminal globular head and the C-terminal coiled-coil rod-like tail .
Arrestin-like, C-terminal (Arrestin-like_C)
Type: Homologous_superfamily

Arrestins comprise a family of closely-related proteins. In addition to the inactivation of G protein-coupled receptors, arrestins have been implicated in the endocytosis of receptors and cross talk with other signalling pathways. S-Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . Beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction . The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold .

This superfamily represents the C-terminal domain of arrestin, and Vacuolar protein sorting protein 26 (VPS26), consisting of an immunoglobulin-like β-sandwich structure.

VPS26 assembles into a multimeric complex with other vacuolar protein sorting proteins (VPSs) and plays a role in vesicular protein sorting .
Arrestin, N-terminal (Arrestin_N)
Type: Homologous_superfamily

G protein-coupled receptors are a large family of signalling molecules that respond to a wide variety of extracellular stimuli. The receptors relay the information encoded by the ligand through the activation of heterotrimeric G proteins and intracellular effector molecules. To ensure the appropriate regulation of the signalling cascade, it is vital to properly inactivate the receptor. This inactivation is achieved, in part, by the binding of a soluble protein, arrestin, which uncouples the receptor from the downstream G protein after the receptors are phosphorylated by G protein-coupled receptor kinases. In addition to the inactivation of G protein-coupled receptors, arrestins have also been implicated in the endocytosis of receptors and cross talk with other signalling pathways. Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . The protein binds calcium, and shows similarity in its C terminus to alpha-transducin and other purine nucleotide-binding proteins. In mammals, arrestin is associated with autoimmune uveitis.

Arrestins comprise a family of closely-related proteins that includes beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction .

The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold . The binding region for phosphorylated light-activated rhodopsin is located at the N-terminal domain, as indicated by the docking of the photoreceptor to the three-dimensional structure of arrestin.

The N-terminal domain consists of an immunoglobulin-like β-sandwich structure.
Copper resistance protein CopC/internalin, immunoglobulin-like (Cu-Rt/internalin_Ig-like)
Type: Homologous_superfamily

This superfamily represents an immunoglobulin E-set-like β-barrel domain found in the following proteins:

Copper-resistance proteins CopC and PcoC. CopC is a bacterial copper protein involved in copper homeostasis that binds 1 equivalent of copper (II). Its immunoglobulin-like fold is similar to that of the unrelated blue copper proteins . PcoC is a plasmid-encoded, soluble, periplasmic protein that is essential for copper resistance in
Escherichia coli .

Internalin proteins InlA, InlB,InlI and InlJ. These proteins are members of a family of listerial cell surface proteins from the opportunistic pathogen Listeria monocytogenes. Their N-terminal regions consist of a central LRR region flanked by an EF-hand-like cap on one end, and an immunoglobulin-like fold on the other. Together these regions form a domain that directs host cell-specific invasion .

Pullulanase A, involved in the degradation of glycogen of the mammalian host cells .
Transcription regulator IclR, C-terminal (Tscrpt_reg_IclR_C)
Type: Domain

Many bacterial transcription regulation proteins which bind DNA through a 'helix-turn-helix' motif can be classified into subfamilies on the basis of sequence similarities. One of these subfamilies, called 'iclR', groups several proteins including:

gylR, a possible activator protein for the gylABX glycerol operon in Streptomyces.

iclR, the repressor of the acetate operon (also known as glyoxylate bypass operon) in Escherichia coli and Salmonella typhimurium.

These proteins have a Helix-Turn-Helix motif at the N terminus that is similar to that of other DNA-binding proteins . This entry represents their C-terminal domain, which shares protein structural similarity with the GAF-like domain. This domain binds to regulatory substrates including glyoxylate, allantoin/ate, indole, aromatic hydrocarbons, sugar acids, succinic semialdehyde, benzoate derivatives, ascorbic acid, glycerol-3-phosphate, glyceraldehyde-3-phosphate and pyruvate .
Methionyl-tRNA synthetase (Met-tRNA_synth)
Type: Family

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

Methionine-tRNA ligase (

) is an alpha 2 dimer. In some species (archaea, eubacteria and eukaryotes) a coding sequence, similar to the C-terminal end of MetRS, is present as an independent gene which is a tRNA binding domain as a dimer. In eubacteria, MetRS can also be split in two sub-classes corresponding to the presence of one or two CXXC domains specific to zinc binding. The crystal structures of a number of methionine-tRNA ligases are known .
Helicase, superfamily 3, single-stranded RNA virus (Helicase_SF3_ssRNA_vir)
Type: Domain

Helicases have been classified in 5 superfamilies (SF1-SF5). All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop) and Walker B (Mg2+-binding aspartic acid) motifs. Superfamily 3 consists of helicases encoded mainly by small DNA viruses and some large nucleocytoplasmic DNA viruses . Small viruses are very dependent on the host-cell machinery to replicate. SF3 helicase in small viruses is associated with an origin-binding domain. By pairing a domain that recognises the ori with a helicase, the virus can bypass the host-cell-based regulation pathway and initiate its own replication. The protein binds to the viral ori leading to origin unwinding. Cellular replication proteins are then recruited to the ori and the viral DNA is replicated.

In SF3 helicases the Walker A and Walker B motifs are separated by spacers of rather uniform, and relatively short, length. In addition to the A and B motifs this family is characterised by a third motif (C) which resides between the B motif and the C terminus of the conserved region. This motif consists of an Asn residue preceded by a run of hydrophobic residues .

Several structures of SF3 helicases have been solved . They all possess the same core α/β fold, consisting of a five-stranded parallel β sheet flanked on both sides by several α helices. In contrast to SF1 and SF2 helicases, which have RecA-like core folds, the strand connectivity within the α/β core domain is that of AAA+ proteins . The SF3 helicase proteins assemble into a hexameric ring.

Some proteins known to contain an SF3 helicase domain are listed below:

Polyomavirus large T antigen. It initiates DNA unwinding and replication via interactions with the viral origin of replication.

Papillomavirus E1 protein. An ATP-dependent DNA helicase required for initiation of viral DNA replication.

Parvovirus Rep/NS1 protein, which is also required for the initiation of viral replication.

Poxviridae and other large DNA viruses D5 protein.

Bacteriophage DNA primase/helicase protein.

Bacterial prophage DNA primase/helicase protein.

The entry represents the core α/β fold of the SF3 helicase domain from predominantly single-stranded RNA viruses.
Serum albumin, N-terminal (Serum_albumin_N)
Type: Domain

A number of serum transport proteins are known to be evolutionarily related, including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin . Albumin is the main protein of plasma; it binds water, cations (such as Ca
2+
, Na
+
and K
+
), fatty acids, hormones, bilirubin and drugs - its main function is to regulate the colloidal osmotic pressure of blood. Alphafeto- protein (alpha-fetoglobulin) is a foetal plasma protein that binds various cations, fatty acids and bilirubin. Vitamin D-binding protein binds to vitamin D and its metabolites, as well as to fatty acids. The biological role of afamin (alpha-albumin) has not yet been characterised. The 3D structure of human serum albumin has been determined by X-ray crystallography to a resolution of 2.8A . It comprises three homologous domains that assemble to form a heart-shaped molecule . Each domain is a product of two subdomains that possess common structural motifs . The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. Structurally, the serum albumins are similar, each domain containing five or six internal disulphide bonds, as shown schematically below:

+---+ +----+ +-----+
| | | | | |
xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |
+-----------------+ +-----+ +---------------+
DNA mismatch repair, conserved site (DNA_mismatch_repair_CS)
Type: Conserved_site

Mismatch repair contributes to the overall fidelity of DNA replication . It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The sequence of some proteins involved in mismatch repair in different organisms have been found to be evolutionarily related. These proteins include:

Escherichia coli and Salmonella typhimurium mutL protein . MutL is required for dam-dependent methyl-directed DNA repair.

Streptococcus pneumoniae hexB protein . The Hex system is nick directed.

Yeast proteins PMS1 and MLH1 .

Human protein MLH1 which is involved in a form of familial hereditary nonpolyposis colon cancer (HNPCC).

This entry represents a perfectly conserved heptapeptide which is located in the N-terminal section of these proteins.
Defective-in-cullin neddylation protein (DCN-prot)
Type: Family

The eukaryotic defective in cullin neddylation (DCN) protein family, contributes to neddylation of cullin components of SCF-type E3 ubiquitin ligase complexes. These multi-protein complexes are required for polyubiquitination and subsequent degradation of target proteins by the 26S proteasome . Proteins in the DCN family include:

Yeast DCN1.

Vertebrate DCN1-like protein 1-5.

Plant Defective in cullin neddylation protein AAR3 .

DCN family proteins all contain a Potentiating neddylation (PONY) domain (

), contains a cullin-binding surface within its C-terminal region and is sufficient to promote neddylation . The N-terminal region of the protein often contains a UBA-like domain.
Diaphanous autoregulatory domain (DAD_dom)
Type: Domain

Formins participate in the assembly of the actin and microtubule cytoskeletons in processes like cell division, migration, and development. Diaphanous-related formins (DRF) contain an N-terminal GTPase-binding domain (GBD) and a C-terminal diaphanous autoregulatory domain (DAD). DRFs are regulated by an autoinhibitory interaction of the C-terminal DAD with the DRF N-terminal armadillo repeat-like region (see

) in the DID or GBD/FH3 domain . This autoinhibition is released upon competitive binding of an activated Rho GTPase to the GBD. The release of DAD allows the catalytical formin homology 2 (FH2) domain to then nucleate and elongate nonbranched actin filaments.

The DAD domain is a ~32 amino acid autoinhibitory domain, which facilitates intramolecular binding. The DAD core forms an α-helical structure and the C-terminal part of the domain contains several basic residues that form a basic region .

Proteins known to contain a DAD domain include:

Fruit fly protein diaphanous, which plays an important role during cytokinesis.

Mammalian diaphanous-related formins (DRF) 1-3, which act as Rho GTPase effectors during cytoskeletal remodelling.

Saccharomyces cerevisiae (Baker's yeast) proteins BNI1 and BNI1-related protein 1 (BNR1).

Emericella nidulans (Aspergillus nidulans) cytokinesis protein sepA, which participates in two actin-mediated processes, septum formation and polarized growth.

Mammalian disheveled-associated activator of morphogenesis (DAAM) proteins.

Mammalian formin-like 1 protein (Fmnl1) or formin-related protein gene in leukocytes (FRL).
Rho GTPase-binding/formin homology 3 (GBD/FH3) domain (GBD/FH3_dom)
Type: Domain

Formins are multidomain proteins conserved from plants to fungi and vertebrates. Due to their pivotal role in the organisation of the actin cytoskeleton formins are involved in processes as diverse as formation of filopodia, microspikes and lamellipodia, establishment and maintenance of cell polarity, vesicular trafficking, formation of adherens junctions, cytokinesis, embryonic development and signalling to the nucleus. Formins are defined by a conserved formin homology 2 (FH2) domain with actin nucleation activity preceded by a proline-rich formin homology 1 (FH1) domain. In most fungal and metazoan formins the FH1-FH2 core is accompanied by a less conserved N-terminal formin homology 3 (FH3) domain involved in targeting . The Diaphanous-related formins are able to interact with activated Rho GTPases through a poorly defined N-terminal Rho GTPase binding domain (GBD) that overlaps with the formin homology 3 (FH3) domain. This binding releases the intramolecular inhibitory interaction between the GBD and a C-terminal Diaphanous autoregulatory domain (DAD) (see

) and renders the protein active. It has been proposed that the GBD and FH3 domains constitute a single domain also found in Dictyostelium guanine nucleotide exchange factors (RasGEFs) .

This entry represents the GBD/FH3 domain that is approximately 380 residues in length. Its role appears to be twofold. On one hand the N-terminal region of formins is involved in subcellular localisation through interaction with diverse targets. The low degree of sequence conservation of this region might correlate with the diversity of binding partners, not only Rho GTPases, and subcellular localisation patterns. On the other hand the GBD/FH3 domain is involved in regulation of activation by releasing of an intramolecular interaction between the DAD and the N terminus . The GBD/FH3 domain is exclusively α-helical and is comprised of the N-terminal part of the GBD, an armadillo repeat region (ARR) and dimerisation subdomains .