SII-SWORD/CoKE huggingface dataset:
PDGF/VEGF domain (PDGF/VEGF_dom)
Type: Domain

Platelet-derived growth factor (PDGF) is a potent mitogen for cells of mesenchymal origin, including smooth muscle cells and glial cells. In both mouse and human, the PDGF signalling network consists of four ligands, PDGFA-D, and two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked
homodimers, but only PDGFA and B can form functional heterodimers. PDGFRs also function as homo- and heterodimers. All known PDGFs have characteristic 'PDGF domains', which include eight conserved cysteines that are involved in inter- and intramolecular bonds. Alternate splicing of the A chain transcript can give rise to two different forms that differ only in their C-terminal extremity. The transforming protein of Woolly monkey sarcoma virus (WMSV) (Simian sarcoma virus), encoded by the v-sis oncogene, is derived from the B chain of PDGF.

PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During later maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal .

Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C) which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis . VEGF is a potent mitogen in embryonic and somatic angiogenesis with a unique specificity for vascular endothelial cells. VEGF forms homodimers and exists in 4 different isoforms. Overall, the VEGF monomer resembles that of PDGF, but its N-terminal segment is helical rather than extended.

PDGF is structurally related to a number of other growth factors which also form disulphide-linked homo- or heterodimers. A cysteine knot motif is a common feature of this domain .
Alpha/beta hydrolase fold-1 (AB_hydrolase_1)
Type: Domain

This entry represents fold-1 of α/β hydrolases.

The α/β hydrolase fold is common to a number of hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is an α/β-sheet (rather than a barrel), containing 8 strands connected by helices . The enzymes are believed to have diverged from a common ancestor, preserving the arrangement of the catalytic residues. All have a catalytic triad, the elements of which are borne on loops, which are the best conserved structural features of the fold. Esterase (EST) from Pseudomonas putida is a member of the α/β hydrolase fold superfamily of enzymes .

In most of the family members the β-strands are parallel, but some have an inversion of the first strands, which gives it an antiparallel orientation. The catalytic triad residues are presented on loops. One of these is the nucleophile elbow and is the most conserved feature of the fold. Some other members lack one or all of the catalytic residues. Some members are therefore inactive but others are involved in surface recognition. The ESTHER database gathers and annotates all the published information related to gene and protein sequences of this superfamily .
Apolipoprotein A/E (ApoA_E)
Type: Family

Exchangeable apolipoproteins (apoA, apoC and apoE) have the same genomic structure and are members of a multi-gene family that probably evolved from a common ancestral gene. This entry includes the ApoA1, ApoA4, Apo5 and ApoE proteins. ApoA1, ApoA4 and Apo5 are part of the APOA1/C3/A4/A5 gene cluster on chromosome 11 . Apolipoproteins function in lipid transport as structural components of lipoprotein particles, cofactors for enzymes and ligands for cell-surface receptors. In particular, apoA1 is the major protein component of high-density lipoproteins; apoA4 is thought to act primarily in intestinal lipid absorption; and apoE is a blood plasma protein that mediates the transport and uptake of cholesterol and lipid by way of its high affinity interaction with different cellular receptors, including the low-density lipoprotein (LDL) receptor. Recent findings with apoA1 and apoE suggest that the tertiary structures of these two members of the human exchangeable apolipoprotein gene family are related . The three-dimensional structure of the LDL receptor-binding domain of apoE indicates that the protein forms an unusually elongated four-helix bundle that may be stabilised by a tightly packed hydrophobic core that includes leucine zipper-type interactions and by numerous salt bridges on the mostly charged surface. Basic amino acids important for LDL receptor binding are clustered into a surface patch on one long helix .
K/Cl co-transporter (KCL_cotranspt)
Type: Family

K+Cl- cotransporters (KCCs) belong to the SLC12 family and act as electroneutral symporters of K+ and Cl- ions across the plasma membrane . They are major determinants of osmotic homeostasis. They are involved in the regulatory volume decrease in response to cell swelling in red blood cells, and have been proposed to play a role in the vectorial movement of Cl
-
across kidney epithelia. The transport process involves one for one electroneutral movement of K
+
together with Cl
-
, and, in all known mammalian cells, the net movement is outward .

In neurones, it appears to play a unique role in maintaining low intracellular Cl
-
concentration, which is required for the functioning of Cl
-
dependent fast synaptic inhibition, mediated by certain neurotransmitters, such as gamma-aminobutyric acid (GABA) and glycine.

Four isoforms of KCC have been identified: KCC1, KCC2, KCC3, and KCC4. The four KCC isoforms share a common protein structure with a central core of twelve hydrophobic transmembrane domains . Comparison of their sequences with those of other ion-transporting membrane proteins reveals that they are part of a new superfamily of cation-chloride co-transporters, which includes the Na-Cl and Na-K-2Cl co-transporters. KCC1 is widely expressed in human tissues, while KCC2 is expressed only in brain neurones, making it likely that this is the isoform responsible for maintaining low Cl
-
concentration in neurones .
Large ribosomal subunit protein eL39 (Ribosomal_eL39)
Type: Family

A number of eukaryotic and archaebacterial large subunit ribosomal proteins can be grouped on the basis of sequence similarities. This entry represents the large ribosomal subunit protein eL39, of about 50 residues long, being the smallest protein of eukaryotic-type ribosomes. In mammals, eL39 has been described as the RNA-binding component of the large ribosomal subunit .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
High mobility group protein HMGN (HMGN_fam)
Type: Family

This entry represents the HMGN family, whose members promote chromatin unfolding, enhance access to nucleosomes, and modulate transcription from chromatin templates. HMGNs are expressed only in vertebrates .

The high mobility group (HMG) proteins are the most abundant and ubiquitous nonhistone chromosomal proteins. They bind to DNA and to nucleosomes and are involved in the regulation of DNA-dependent processes such as transcription, replication, recombination, and DNA repair. They can be grouped into three families: HMGB (HMG 1/2), HMGN (HMG 14/17) and HMGA (HMG I/Y). The characteristic domains are: AT-hook for the HMGA family, the HMG Box for the HMGB family, and the nucleosome-binding domain (NBD) for the members of the HMGN family .
SEA domain (SEA_dom)
Type: Domain

The SEA domain has been named after the first three proteins in which it was identified (Sperm protein, Enterokinase and Agrin). The SEA domain has around 120 residues, it is an extracellular domain found in a number of cell surface and secreted proteins in which it could be present in one or two copies . Many SEA domains possess autoproteolysis activity. The SEA domain is closely associated with regions receiving extensive O-glycosylation and is present adjacent to the transmembrane segment in quite a number of type I transmembrane proteins on the cell surface, such as mucin-1 (MUC1) and Notch receptors and in type II single-pass transmembrane proteins such as enterokinase and matriptases. It also present in interphotoreceptor matrix proteoglycans (IMPG1 and IMPG2) . It has been proposed that carbohydrates are required to stabilise SEA domains and protect them against proteolytic degradation and that the extent of substitution may control proteolytic processing .

The SEA domain contains an about 80-residue conserved region and an about 40-residue segment that separates the conserved region from the subsequent C-terminal domains with an alternating conformation of β-sheets and α-helices. Structural analysis of MUC1 SEA domain revealed that it adopts a ferredoxin-like fold in which the cleavage site is located in the middle of the β-hairpin of the second and third β-strands. MUC1 SEA domain undergoes autoproteolysis at the glycine-serine peptide bond and the Ser responsible of this activity is located in the consensus motif GSXXX (X: a hydrophobic residue) .

Some proteins known to contain a SEA domain include:

Vertebrate agrin, an heparan sulfate proteoglycan of the basal lamina of the neuromuscular junction. It is responsible for the clustering of acetylcholine receptors (AChRs) and other proteins at the neuromuscular junction.

Mammalian enterokinase. It catalyses the conversion of trypsinogen to trypsin which in turn activates other proenzymes, including chymotrypsinogen, procarboxypeptidases, and proelastases.

63kDa sea urchin sperm protein (SP63). It might mediate sperm-egg or sperm-matrix interactions.

Animal perlecan, a heparan sulfate containing proteoglycan found in all basement membranes. It interacts with other basement membrane components such as laminin and collagen type IV and serves as an attachment substrate for cells.

Some vertebrate epithelial mucins. They form a family of secreted and cell surface glycoproteins expressed by epithelial tissues and implicated in epithelial cell protection, adhesion modulation and signaling.

Mammalian cell surface antigen 114/A10, an integral transmembrane protein that is highly expressed in hematopoietic progenitor cells and IL-3-dependent cell lines.
Fibronectin, type I (Fibronectin_type1)
Type: Domain

Fibronectin type I repeats are one of the three repeats found in the fibronectin protein. Fibronectin is a plasma protein that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Type I domain (FN1) is approximately 40 residues in length. Four conserved cysteines are involved in disulphide bonds. The 3D structure of the FN1 domain has been determined . It consists of two antiparallel β-sheets, first a double-stranded one, that is linked by a disulphide bond to a triple-stranded β-sheet. The second conserved disulphide bridge links the C-terminal adjacent strands of the domain.

In human tissue plasminogen activator chain A the FN1 domain together with the following epidermal growth factor (EGF)-like domain are involved in fibrin-binding . It has been suggested that these two modules form a single structural and functional unit . The two domains keep their specific tertiary structure, but interact intimately to bury a hydrophobic core; the inter-module linker makes up the third strand of the EGF-module's major β-sheet.
PE-PGRS family, N-terminal (PE-PGRS_N)
Type: Domain

This family is named after a PE motif near to the amino terminus. The carboxyl terminus of this family are variable and fall into several classes. The largest class of PE proteins is the highly repetitive PGRS class which have a high glycine content. The function of these proteins is uncertain but it has been suggested that they may be related to antigenic variation of Mycobacterium tuberculosis and also immune modulation .

The human pathogen Mycobacterium tuberculosis harbours a large number of genes that encode proteins whose N-terminals contain the characteristic motifs Pro-Glu (PE) or Pro-Pro-Glu (PPE). These proteins are exported to the bacterial surface via type VII secretion systems known as ESX . A subgroup of the PE proteins contains polymorphic GC-rich sequences (PGRS), while a subgroup of the PPE proteins contains major polymorphic tandem repeats (MPTR). The function of most of these proteins remains unknown . However, the PE_PGRS proteins from Mycobacterium marinum are secreted by components of the ESX-5 system that belongs to the recently defined type VII secretion systems . It has also been reported that the PE_PGRS family of proteins contains multiple calcium-binding and glycine-rich sequence motifs GGXGXD/NXUX. This sequence repeat constitutes a calcium-binding parallel β-roll or parallel β-helix structure and is found in RTX toxins secreted by many Gram-negative bacteria .

PPE51 member has been described as a small molecule-selective channel required for the uptake of nutrients across the outer mycomembrane . This protein transports glycerol and glucose as well as maltose and lactose disaccharides. It is involved in sensitivity to M.tuberculosis growth inhibitory agrichemical 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) and sensitivity to bactericidal thio-disaccharide T-6 compound .
Holliday junction branch migration complex subunit RuvA (RuvA)
Type: Family

In prokaryotes, RuvA, RuvB, and RuvC process the universal DNA intermediate of homologous recombination, termed Holliday junction. The tetrameric DNA helicase RuvA, known as Holliday junction branch migration complex subunit RuvA, specifically binds to the Holliday junction and facilitates the isomerization of the junction from the stacked folded configuration to the square-planar structure . In the RuvA tetramer, each subunit consists of three domains, I, II and III, where I and II form the major core that is responsible for Holliday junction binding and base pair rearrangements of Holliday junction executed at the crossover point, whereas domain III regulates branch migration through direct contact with RuvB.
NUDIX hydrolase domain (NUDIX_hydrolase_dom)
Type: Domain

The Nudix superfamily is widespread among eukaryotes, bacteria, archaea and viruses and consists mainly of pyrophosphohydrolases that act upon substrates of general structure NUcleoside DIphosphate linked to another moiety, X (NDP-X) to yield NMP plus P-X. Such substrates include (d)NTPs (both canonical and oxidised derivatives), nucleotide sugars and alcohols, dinucleoside polyphosphates (NpnN), dinucleotide coenzymes and capped RNAs. However, phosphohydrolase activity, including activity towards NDPs themselves, and non-nucleotide substrates such as diphosphoinositol polyphosphates (DIPs), 5-phosphoribosyl 1-pyrophosphate (PRPP), thiamine pyrophosphate (TPP) and dihydroneopterin triphosphate (DHNTP) have also been described. Some superfamily members, such as Escherichia coli MutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In procaryotes and simple eukaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Nudix hydrolases are typically small proteins, larger ones having additional domains with interactive or other catalytic functions .
Biotin/lipoyl attachment (Biotin_lipoyl)
Type: Domain

The biotin/lipoyl attachment domain has a conserved lysine residue that binds biotin or lipoic acid. The 80 residues surrounding the biotinyl-binding lysine residue display some sequence similarity to that around the lipoyl-binding lysine residue. Biotin plays a catalytic role in some carboxyl transfer reactions and is covalently attached, via an amide bond, to a lysine residue in enzymes requiring this coenzyme . E2 acyltransferases have an essential cofactor, lipoic acid, which is covalently bound via an amide linkage to a lysine group . The lipoic acid cofactor is found in a variety of proteins that include, H-protein of the glycine cleavage system (GCS), mammalian and yeast pyruvate dehydrogenases and branched-chain 2-oxo acid dehydrogenase complex (BCOADC).

The lipoyl domains of 2-oxo acid dehydrogenase multienzyme complexes and the biotinyl domains of biotin-dependent enzymes have been solved, which revealed that they have homologous structures consisting of a flattened 8-stranded -barrel with the target lysine positioned in comparable β-turns. Additional important residues for specificity have been identified, such as the conserved methionine flanking the target lysine that is essential for the recognition of the biotinyl domain by the biotinyl protein ligase .
Flagellar motor switch protein FliG (Flg_Motor_Flig)
Type: Family

The flagellar motor switch in Escherichia coli and Salmonella typhimurium regulates the direction of flagellar rotation and hence controls swimming behaviour . The switch is a complex apparatus that responds to signals transduced by the chemotaxis sensory signalling system during chemotactic behaviour . CheY, the chemotaxis response regulator, is believed to act directly on the switch to induce tumbles in the swimming pattern, but no physical interactions of CheY and switch proteins have yet been demonstrated.
Polyprenyl synthetase-like (Polyprenyl_synt)
Type: Family

This entry includes a group of polyprenyl synthetase enzymes from all cellular organisms. It has been shown that these enzymes share some regions of sequence similarity. From 3D structure analysis, it was revealed that they also share structure and reaction mechanisms, using similar strategies for substrate binding and catalysis .

This entry also includes Bifunctional sesterterpene synthases and Bifunctional terpene synthase FUP1 from Fusarium proliferatum, which is involved in mycotoxin fusaproliferin biosynthesis .

A variety of isoprenoid compounds are synthesised by various organisms. For example in eukaryotes the isoprenoid biosynthetic pathway is responsible for the synthesis of a variety of end products including cholesterol, dolichol, ubiquinone or coenzyme Q. In bacteria this pathway leads to the synthesis of isopentenyl tRNA, isoprenoid quinones, and sugar carrier lipids. Among the enzymes that participate in that pathway, are a number of polyprenyl synthetase enzymes which catalyse a 1'4-condensation between 5 carbon isoprene units.
DNA recombination protein RecR (DNA_Rcmb_RecR)
Type: Family

The bacterial protein RecR is an important regulator in the RecFOR homologous recombination pathway during DNA repair . It acts with RecF and RecO forming a complex that facilitates the loading of RecA onto ssDNA . RecR is a zinc metalloprotein consisting of a N-terminal helix-hairpin-helix (HhH) motif, a middle region containing a zinc finger motif and a Toprim domain, and a C-terminal domain comprising a divergent Walker B motif and a C-terminal helix .
CRIB domain (CRIB_dom)
Type: Domain

This entry represents the CRIB domain.

Many putative downstream effectors of the small GTPases Cdc42 and Rac contain a GTPase binding domain (GBD), also called p21 binding domain (PBD), which has been shown to specifically bind the GTP bound form of Cdc42 or Rac, with a preference for Cdc42 . The most conserved region of GBD/PBD domains is the N-terminal Cdc42/Rac interactive binding motif (CRIB), which consists of about 16 amino acids with the consensus sequence I-S-x-P-x(2,4)-F-x-H-x(2)-H-V-G .

Although the CRIB motif is necessary for the binding to Cdc42 and Rac, it is not sufficient to give high-affinity binding . A less well conserved inhibitory switch (IS) domain responsible for maintaining the proteins in a basal (autoinhibited) state is located at the C-terminal of the CRIB-motif .

GBD domains can adopt related but distinct folds depending on context. Although GBD domains are largely unstructured in the free state, the IS domain forms an N-terminal β-hairpin that immediately follows the conserved CRIB motif and a central bundle of three α-helices in the autoinhibited state. The interaction between GBD domains and their respective G proteins leads to the formation of a high-affinity complex in which unstructured regions of both the effector and the G protein become rigid. CRIB motifs from various GBD domains interact with Cdc42 in a similar manner, forming an intermolecular β-sheet with strand β2 of Cdc42. Outside the CRIB motif, the C-terminal of the various GBD domains are very divergent and show variation in their mode of binding to Cdc42, perhaps determining the specificity of the interaction. Binding of Cdc42 or Rac to the GBD domain causes a dramatic conformational change, refolding part of the IS domain and unfolding the rest .

Some proteins known to contain a CRIB domain are listed below:

Mammalian activated Cdc42-associated kinases (ACKs), nonreceptor tyrosine kinases implicated in integrin-coupled pathways.

Mammalian p21-activated kinases (PAK1 to PAK4), serine/threonine kinases that modulate cytoskeletal assembly and activate MAP-kinase pathways.

Mammalian Actin nucleation-promoting factor WAS (also known as Wiskott-Aldrich Symdrom Proteins, WASPs), non-kinase proteins involved in the organisation of the actin cytoskeleton.

Yeast STE20 and CLA4, the homologues of mammalian PAKs. STE20 is involved in the mating/pheromone MAP kinase cascade.