SII-SWORD/CoKE huggingface dataset:
Peripheral myelin protein PMP22 (PMP22)
Type: Family

The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities . Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini .

PMP22, also termed growth-arrest specific protein (GAS3), is a structural component of compact myelin in the peripheral nervous system. Aberrant expression of the PMP22 gene, and mutations in the protein, are associated with a variety of hereditary peripheral motor and sensory neuropathies . An intra-chromosomal duplication containing the PMP22 gene is found in the majority of patients suffering from the autosomal dominant demyelinating neuropathy Charcot-Marie-Tooth disease 1A (CMT1A) . In addition, rare point mutations in PMP22 have been found in non-duplication CMT1A patients and in the severe congenital peripheral neuropathy Dejerine-Sottas syndrome .

PMP22 is also implicated in the control of cell proliferation. Its expression levels are up-regulated in cells undergoing growth arrest , and it has been shown that modulating PMP22 levels in cultured Schwann cells exerts a profound effect on the length of the G1 phase of the cell cycle . It has also been demonstrated that over-expression of PMP22 in NIH 3T3 fibroblast cells induces apoptosis .
Potassium channel, voltage dependent, KCNQ (K_chnl_volt-dep_KCNQ)
Type: Family

KCNQ channels (also known as KQT-like channels) differ from other voltage-gated 6 TM helix channels, chiefly in that they possess no tetramerisation domain. Consequently, they rely on interaction with accessory subunits, or form heterotetramers with other members of the family . Currently, 5 members of the KCNQ family are known. These have been found to be widely distributed within the body, having been shown to be expressed in the heart, brain, pancreas, lung, placenta and ear. They were initially cloned as a result of a search for proteins involved in cardiac arhythmia. Subsequently, mutations in other KCNQ family members have been shown to be responsible for some forms of hereditary deafness and benign familial neonatal epilepsy .
Transforming growth factor beta-1 proprotein (TGFb1)
Type: Family

The transforming growth factors-beta constitute a family of multi-functional cytokines that regulate cell growth and differentiation . Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide . TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects.

The solution structure of human TGF-beta 1 was determined using multinuclear magnetic resonance spectroscopy with hybrid distance geometry/simulated annealing . The structure shows a high degree of similarity to that of TGF-beta 2, but with notable differences in structure and flexibility. Examination of TGF-beta 1 mRNA levels in adult murine tissues indicates that expression is predominant in spleen, lung and placenta . TGF-beta 1 is believed to play important roles in pathologic processes.
Transforming growth factor beta-2 proprotein (TGFb2)
Type: Family

The transforming growth factors-beta constitute a family of multi-functional cytokines that regulate cell growth and differentiation . Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide . TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects.

The complete amino acid sequence of human beta 2 transforming growth factor (hTGF-beta 2) has been determined by automated Edman degradation . Human TGF-beta 2 consists of 2 identical disulphide-linked subunits that share a high degree of similarity with the functionally related TGF-beta 1, and reveal lower levels of similarity to porcine inhibins and activins, the C-terminal regions of human Mullerian inhibiting substance, and the putative decapentaplegic gene complex protein of Drosophila melanogaster.

The crystal structure of the TGF-beta 2 monomer lacks a well-defined hydrophobic core and displays an unusual elongated non-globular fold . Eight cysteine residues form 4 intra-chain disulphide bonds, creating the characteristic knotted arrangement. The dimer is stabilised by a ninth cysteine, which forms an inter-chain disulphide bond, and by 2 identical hydrophobic interfaces. Other members of the TGF-beta superfamily, including activins, inhibins and various developmental factors, are also likely to adopt the TGF-β fold.
Left- Right determination factor (LRDF)
Type: Family

Examples of lateral asymmetry are often found in vertebrates (e.g., the heart being on the left side), but the molecular mechanisms governing establishment of left-right (L-R) handedness are unknown . It is now thought that the gene lefty, a member of the transforming growth factor-beta family, may encode a morphogen for L-R determination. Lefty protein, which contains the cysteine-knot motif characteristic of this superfamily, is expressed in the left half of gastrulating mouse embryos. This asymmetric expression is transient and occurs just before the first sign of lateral asymmetry appears]. Thus lefty may be involved in establishing L-R asymmetry in the organ systems of mammals.

Abnormal endometrial bleeding is a common manifestation of gynaecological diseases. A human gene, termed endometrial bleeding associated factor (ebaf), which is expressed strongly in endometrium, has been shown to be associated with abnormal endometrial bleeding . The predicted protein product of ebaf shares similarity with members of TGF-beta superfamily. Thus ebaf is a novel member of the TGF-beta superfamily and an endometrial tissue factor whose expression is associated with normal menstrual and abnormal endometrial bleeding.
Protease-activated receptor 3 (Prot_act_rcpt_3)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partly through an unusual proteolytically activated GPCR . Gene knockout experiments have provided definitive evidence for a second thrombin receptor in mouse platelets and have suggested tissue-specific roles for different thrombin receptors. Because the physiological agonist at the receptor was originally unknown, it was provisionally named protease-activated receptor (PAR) . At least 4 PAR subtypes have now been characterised. Thus, the thrombin and PAR receptors constitute a fledgling receptor family that shares a novel proteolytic activation mechanism .

The human thrombin receptor, designated protease-activated receptor 3 (PAR3), has been cloned and characterised . PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, including human bone marrow and mouse megakaryocytes, making it a candidate for the sought-after second platelet thrombin receptor. PAR3 provides a new tool for understanding thrombin signalling and a possible target for therapeutics designed selectively to block thrombotic, inflammatory and proliferative responses to thrombin.
Protease-activated receptor 4 (Prot_act_rcpt_4)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partly through an unusual proteolytically activated GPCR . Gene knockout experiments have provided definitive evidence for a second thrombin receptor in mouse platelets and have suggested tissue-specific roles for different thrombin receptors. Because the physiological agonist at the receptor was originally unknown, it was provisionally named protease-activated receptor (PAR) . At least 4 PAR subtypes have now been characterised. Thus, the thrombin and PAR receptors constitute a fledgling receptor family that shares a novel proteolytic activation mechanism .

The human thrombin receptor, designated protease-activated receptor 4 (PAR4), has been cloned and characterised . Northern blot analysis showed that PAR4 mRNA was expressed in a number of tissues, high levels being present in lung, pancreas, thyroid, testis and small intestine. Using fluorescence in situ hybridisation, the human PAR4 gene has been mapped to chromosome 19p12 .
NADH-quinone oxidoreductase, chain 5-like (NU5C-like)
Type: Family

NADH-quinone oxidoreductase chain 5 is part of the NADH-ubiquinone oxidoreductase (complex I), which catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane :

NADH + ubiquinone = NAD(+) + ubiquinol

This family includes NAD(P)H-quinone oxidoreductase subunit 5, organellar chromatophore 2 from the amoeba Paulinella chromatophora, which carries cyanobacterial genes in its cell nucleus .

Probable inorganic carbon transporter subunit DabB is also part of this protein family. The sequence of this protein has been reported to be distantly related to complex I and cyanobacterial CO2-uptake system subunits. Homology between DabB and complex I subunits suggests cation transport without implying redox activity .
Fumarate reductase/succinate dehydrogenase, FAD-binding site (FRD_SDH_FAD_BS)
Type: Binding_site

In bacteria two distinct, membrane-bound, enzyme complexes are responsible for the interconversion of fumarate and succinate (

): fumarate reductase (Frd) is used in anaerobic growth, and succinate dehydrogenase (Sdh) is used in aerobic growth. Both complexes consist of two main components: a membrane-extrinsic component composed of a FAD-binding flavoprotein and an iron-sulphur protein; and an hydrophobic component composed of a membrane anchor protein and/or a cytochrome B.

In eukaryotes mitochondrial succinate dehydrogenase (ubiquinone) (

) is an enzyme composed of two subunits: a FAD flavoprotein and and iron-sulphur protein.

The flavoprotein subunit is a protein of about 60 to 70 Kd to which FAD is covalently bound to a histidine residue which is located in the N-terminal section of the protein . The sequence around that histidine is well conserved in Frd and Sdh from various bacterial and eukaryotic species .
FAD-dependent oxidoreductase 2, FAD-binding domain (FAD-dep_OxRdtase_2_FAD-bd)
Type: Domain

This domain is found in proteins that bind FAD, mainly in FAD-dependent oxidoreductase family 2 proteins, such as the flavoprotein subunits from succinate and fumarate dehydrogenase, and aspartate oxidase .
RNA recognition motif domain, eukaryotic-type (RRM_euk-type)
Type: Domain

Many eukaryotic proteins that are known or supposed to bind single-stranded RNA contain one or more copies of a putative RNA-binding domain of about 90 amino acids. This is known as the eukaryotic putative RNA-binding region RNP-1 motif , or RNA recognition motif (RRM). RRMs are found in a variety of RNA binding proteins, including heterogeneous nuclear ribonucleoproteins (hnRNPs), proteins implicated in regulation of alternative splicing, and protein components of small nuclear ribonucleoproteins (snRNPs). The motif also appears in a few single stranded DNA binding proteins. The RRM structure consists of four strands and two helices arranged in an α/β sandwich, with a third helix present during RNA binding in some cases .
Transcription factor, NFYB/HAP3, conserved site (Transcrpt_fac_NFYB/HAP3_CS)
Type: Conserved_site

The CCAAT-binding factor (CBF, of NFY) is a mammalian transcription factor that binds to a CCAAT motif in the promoters of a wide variety of genes, including type I collagen and albumin. The factor is a heteromeric complex of A and B subunits, both of which are required for DNA-binding . The subunits can interact in the absence of DNA-binding, conserved regions in each being important in mediating this interaction.

The A subunit can be split into 3 domains on the basis of sequence similarity, a non-conserved N-terminal 'A domain'; a highly-conserved central 'B domain' involved in DNA-binding; and a C-terminal 'C domain', which contains a number of glutamine and acidic residues involved in protein-protein interactions . The A subunit shows striking similarity to the HAP3 subunit of the yeast CCAAT-binding heterotrimeric transcription factor . The Kluyveromyces lactis HAP3 protein has been predicted to contain a 4-cysteine zinc finger, which is thought to be present in similar HAP3 and CBF subunit A proteins, in which the third cysteine is replaced by a serine .
Transcription factor CBF/NF-Y/archaeal histone domain (CBFA_NFYB_domain)
Type: Domain

This domain is found in archaebacterial histones and histone-like transcription factors from eukaryotes.
ATPase, AAA-type, core (ATPase_AAA_core)
Type: Domain

AAA ATPases (ATPases Associated with diverse cellular Activities) form a large protein family and play a number of roles in the cell including cell-cycle regulation, protein proteolysis and disaggregation, organelle biogenesis and intracellular transport. Some of them function as molecular chaperones, subunits of proteolytic complexes or independent proteases (FtsH, Lon). They also act as DNA helicases and transcription factors .

AAA ATPases belong to the AAA+ superfamily of ringshaped P-loop NTPases, which act via the energy-dependent unfolding of macromolecules . There are six major clades of AAA domains (proteasome subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains, the MSP1/katanin/spastin group and BCS1 and it homologues), as well as a number of deeply branching minor clades .

They assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore. These proteins produce a molecular motor that couples ATP binding and hydrolysis to changes in conformational states that act upon a target substrate, either translocating or remodelling it .

They are found in all living organisms and share the common feature of the presence of a highly conserved AAA domain called the AAA module. This domain is responsible for ATP binding and hydrolysis. It contains 200-250 residues, among them there are two classical motifs, Walker A (GX4GKT) and Walker B (HyDE) .

The functional variety seen between AAA ATPases is in part due to their extensive number of accessory domains and factors, and to their variable organisation within oligomeric assemblies, in addition to changes in key functional residues within the ATPase domain itself.
ATPase, AAA-type, conserved site (ATPase_AAA_CS)
Type: Conserved_site

The functional variety seen between AAA ATPases is in part due to their extensive number of accessory domains and factors, and to their variable organisation within oligomeric assemblies, in addition to changes in key functional residues within the ATPase domain itself.

This entry covers a highly conserved region in the central part of the ATPase domain that is distinct from motifs A and B.

AAA ATPases (ATPases Associated with diverse cellular Activities) form a large protein family and play a number of roles in the cell including cell-cycle regulation, protein proteolysis and disaggregation, organelle biogenesis and intracellular transport. Some of them function as molecular chaperones, subunits of proteolytic complexes or independent proteases (FtsH, Lon). They also act as DNA helicases and transcription factors .

AAA ATPases belong to the AAA+ superfamily of ringshaped P-loop NTPases, which act via the energy-dependent unfolding of macromolecules . There are six major clades of AAA domains (proteasome subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains, the MSP1/katanin/spastin group and BCS1 and it homologues), as well as a number of deeply branching minor clades .

They assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore. These proteins produce a molecular motor that couples ATP binding and hydrolysis to changes in conformational states that act upon a target substrate, either translocating or remodelling it .

They are found in all living organisms and share the common feature of the presence of a highly conserved AAA domain called the AAA module. This domain is responsible for ATP binding and hydrolysis. It contains 200-250 residues, among them there are two classical motifs, Walker A (GX4GKT) and Walker B (HyDE) .
Fibronectin type III (FN3_dom)
Type: Domain

Fibronectin is a dimeric glycoprotein composed of disulfide-linked subunits
with a molecular weight of 220-250kDa each. It is involved in cell adhesion,
cell morphology, thrombosis, cell migration, and embryonic differentiation. Fibronectin is a modular protein composed of homologous repeats of three
prototypical types of domains known as types I, II, and III .

Fibronectin type-III (FN3) repeats are both the largest and the most common of the fibronectin subdomains. Domains homologous to FN3 repeats have been found
in various animal protein families including other extracellular-matrix
molecules, cell-surface receptors, enzymes, and muscle proteins . Structures of individual FN3 domains have revealed a conserved β-sandwich fold with one β-sheet containing four strands and the other sheet containing three strands (see for example

) . This fold is topologically very similar to that of Ig-like domains, with a notable difference being the lack of a conserved disulfide bond in FN3 domains. Distinctive hydrophobic core packing and the lack of detectable
sequence homology between immunoglobulin and FN3 domains suggest, however,
that these domains are not evolutionarily related .

FN3 exhibits functional as well as structural modularity. Sites of interaction with other molecules have been mapped to short stretch of amino acids such as the Arg-Gly-Asp (RGD) sequence found in various FN3 domains. The RGD sequences is involved in interactions with integrin. Small peptides containing the RGD sequence can modulate a variety of cell adhesion invents associated with thrombosis, inflammation, and tumour metastasis. These properties have led to the investigation of RGD peptides and RGD peptide analogues as potential therapeutic agents .
Bi-component toxin, staphylococci (Bi-component_toxin_staph)
Type: Family

Many virulence mechanisms are employed by Staphylococci to induce pathogenesis: these can include polysaccharide capsules and exotoxins . Examples of the latter are bi-component toxins, which involve the synergistic combination of an "S" and an "F" component. These undergo conformational changes in their protein structure and form oligomeric pores in the target cell membrane upon recognition of certain host receptors. The main cells targeted are polymorphonuclear cells, monocytes, erythrocytes and macrophages. Examples of this protein family include: leucocidin, gamma-hemolysin and alpha-hemolysin .
Carbamate kinase (Carb_kinase)
Type: Family

The arginine dihydrolase (AD) pathway is found in many prokaryotes and some primitive eukaryotes. The three- enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon dioxide and ammonia. In simpler bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein .

Carbamate kinase is involved in the last step of the AD pathway, converting carbamoyl phosphate and ADP into ammonia, carbon dioxide and ATP . The second step of the pathway involves the degradation of L-citrulline to carbamoyl phosphate and L-ornithine, using ornithine carbamoyltransferase .

The crystal structure of Enterococcus faecium carbamate kinase has been determined to 2.8A resolution . The enzyme exists as a homodimer of two 33kDa subunits. The hallmark of the dimer is a 16-stranded β-sheet, surrounded by α-helices. Each subunit contains an active site within a large crevice.