SII-SWORD/CoKE huggingface dataset:
ATPase, OSCP/delta subunit (ATPase_OSCP/dsu)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This family represents subunits called delta in bacterial and chloroplast ATPase, or OSCP (oligomycin sensitivity conferral protein) in mitochondrial ATPase (note that in mitochondria there is a different delta subunit,

). The OSCP/delta subunit appears to be part of the peripheral stalk that holds the F1 complex alpha3beta3 catalytic core stationary against the torque of the rotating central stalk, and links subunit A of the F0 complex with the F1 complex. In mitochondria, the peripheral stalk consists of OSCP, as well as F0 components F6, B and D. In bacteria and chloroplasts the peripheral stalks have different subunit compositions: delta and two copies of F0 component B (bacteria), or delta and F0 components B and B' (chloroplasts) .
Mur ligase, N-terminal catalytic domain (Mur_ligase_N)
Type: Domain

The bacterial cell wall provides strength and rigidity to counteract internal osmotic pressure, and protection against the environment. The peptidoglycan layer gives the cell wall its strength, and helps maintain the overall shape of the cell. The basic peptidoglycan structure of both Gram-positive and Gram-negative bacteria is comprised of a sheet of glycan chains connected by short cross-linking polypeptides. Biosynthesis of peptidoglycan is a multi-step (11-12 steps) process comprising three main stages:

(1) formation of UDP-N-acetylmuramic acid (UDPMurNAc) from N-acetylglucosamine (GlcNAc).

(2) addition of a short polypeptide chain to the UDPMurNAc.

(3) addition of a second GlcNAc to the disaccharide-pentapeptide building block and transport of this unit through the cytoplasmic membrane and incorporation into the growing peptidoglycan layer.

Stage two involves four key Mur ligase enzymes: MurC (

) , MurD (

) , MurE (

) and MurF (

) . These four Mur ligases are responsible for the successive additions of L-alanine, D-glutamate, meso-diaminopimelate or L-lysine, and D-alanyl-D-alanine to UDP-N-acetylmuramic acid . All four Mur ligases are topologically similar to one another, even though they display low sequence identity. They are each composed of three domains: an N-terminal Rossmann-fold domain responsible for binding the UDPMurNAc substrate; a central domain (similar to ATP-binding domains of several ATPases and GTPases); and a C-terminal domain (similar to dihydrofolate reductase fold) that binds the incoming amino acid . Residues found in the three domains (the Asp50, Lys130 (GKT motif), and Glu174 residues, MurC numbering) are involved in the catalytic process . The conserved sequence motifs found in the four Mur enzymes also map to other members of the Mur ligase family, including folylpolyglutamate synthetase, cyanophycin synthetase and the capB enzyme from Bacillales .

This entry represents the N-terminal domain of several stage 2 Mur ligases, including: UDP-N-acetylmuramate-L-alanine ligase (MurC),
UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase (MurE), and UDP-N-acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase (MurF).
Equine herpesvirus protein of unknown function (EHV_Unk)
Type: Family

The IR5 open reading frame (ORF) of the Equid herpesvirus 1 (EHV-1) genome maps within the inverted repeat segments. Sequence analyses of the gene region revealed an ORF of 236 amino acids that showed a high degree of similarity to ORF64 of Human herpesvirus 3 (HHV-3) and ORF3 of Equid herpesvirus 4 (EHV-4), both of which map within the inverted repeats, and to the US10 ORF of Human herpesvirus 1 (HHV-1), which maps within the unique short segment. The IR5 ORF houses a sequence of 13 residues (CAYWCCLGHAFAC) that matches perfectly the consensus zinc finger motif (C-X2-4-C-X2-15-C/H-X2-4-C/H) . Putative cis-acting elements flanking the IR5 ORF include a TATA box, a CAAT box, and a polyadenylation signal. Coupled with various experimental data, the IR5 gene of EHV-1 thus exhibits characteristics representative of a late gene of the gamma-1 class. The DNA sequence covering ~70% of the short unique region (Us) and part of the short inverted repeat of the Meleagrid herpesvirus 1 (MeHV-1) GA strain has been determined. Sequence analysis showed the presence of nine potential ORFs in the Us region, four of which were found to be similar to US10 (minor virion protein) .
Glycosyl transferase, family 4 (Glycosyl_transferase_4)
Type: Family

This entry represents a family of UDP-GlcNAc/MurNAc: polyisoprenol-P GlcNAc/MurNAc-1-P transferases. Members of the family include eukaryotic N-acetylglucosamine-1-phosphate transferases, which catalyse the conversion of UDP-N-acteyl-D-glucosamine and dolichyl phosphate to UMP and N-acetyl-D-glucosaminyl-diphosphodolichol in the glycosylation pathway;
and bacterial phospho-N-acetylmuramoyl-pentapeptide-transferases, which catalyse the first step of the lipid cycle reactions in the biosynthesis of cell wall peptidoglycan.
Thyroglobulin type-1 (Thyroglobulin_1)
Type: Domain

Thyroglobulin (Tg) is a large glycoprotein specific to the thyroid gland and is the precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3). The N-terminal section of Tg contains 10 repeats of a domain of about 65 amino acids which is known as the Tg type-1 repeat . Such a domain has also been found as a single or repeated sequence in the HLA class II associated invariant chain ; human pancreatic carcinoma marker proteins GA733-1 and GA733-2 ; nidogen (entactin), a sulphated glycoprotein which is widely distributed in basement membranes and that is tightly associated with laminin; insulin-like growth factor binding proteins (IGFBP) ; saxiphilin, a transferrin-like protein from Rana catesbeiana (Bull frog) that binds specifically to the neurotoxin saxitoxin ; chum salmon egg cysteine proteinase inhibitor, and equistatin, a thiol-protease inhibitor from Actinia equina (sea anemone) . The existence of Thyr-1 domains in such a wide variety of proteins raises questions about their activity and function, and their interactions with neighbouring domains. The Thyr-1 and related domains belong to MEROPS proteinase inhibitor family I31, clan IX.

Equistatin from A. equina is composed of three Thyr-1 domains; as with other proteins that contains Thyr-1 domains, the thyropins, they bind reversibly and tightly to cysteine proteases (inhibitor family C1). In equistatin inhibition of papain is a function of domain-1. Unusually domain-2 inhibits cathepsin D, an aspartic protease (inhibitor family A1) and has no activity against papain. Domain-3, does not inhibit either papain or cathepsin D, and its function or its target peptidase has yet to be determined .
Proteasome component (PCI) domain (PCI_dom)
Type: Domain

The PCI (for Proteasome, COP9, Initiation factor 3) domain (sometimes also referred to as the PINT domain, for Proteasome subunits, Int-6, Nip-1, and Trip-15) is present in six different subunits of 26 proteasome lid, COP9 signalosome (CSN) and eukaryotic translation initiation factor-3 (eIF3) complexes, as well as in subunits of certain other multiprotein complexes. The PCI domain mediates and stabilizes protein-protein interactions within the complexes. The role of the PCI domains is most likely that of a scaffold for the other complex subunits and other binding partners. The PCI domain could play a role as a universal binding domain supporting intra-complex interactions as well as recruitments of additional ligands .

PCI is an ~190-amino acid domain, not well conserved in its primary sequence, usually located near the C terminus of the protein. It does not contain any invariant residues or any conserved pattern of charged residues that would suggest a catalytic activity. The PCI domain is comprised of two subdomains that are intimately connected, an N-terminal helical bundle (HB) subdomain and a C-terminal globular winged helix (WH) subdomain. The C- terminal half of the PCI domain is much better conserved than the N-terminal half .
Peptidase M13 (Peptidase_M13)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family M13 (neprilysin family, clan MA(E)). The M13 family includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA,

), endothelin-converting enzyme I (ECE-1,

), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. The cytoplasmic domain contains a conformationally-restrained octapeptide, which is thought to act as a stop transfer sequence that prevents proteolysis and secretion . Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity . The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH .

M13 peptidases are well-studied proteases found in a wide range of organisms including mammals and bacteria. In mammals they participate in processes such as cardiovascular development, blood-pressure regulation, nervous control of respiration, and regulation of the function of neuropeptides in the central nervous system. In bacteria they may be used for digestion of milk . The family includes eukaryotic and prokaryotic oligopeptidases, as well as some of the proteins responsible for the molecular basis of the blood group antigens e.g. Kell .

ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta. Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homologue of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well. Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition .
Protein kinase domain (Prot_kinase_dom)
Type: Domain

This entry represents the protein kinase domain containing the catalytic function of protein kinases . This domain is found in serine/threonine-protein kinases, tyrosine-protein kinases and dual specificity protein kinases.

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue which is important for the catalytic activity of the enzyme .

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Peptidylglycine alpha-hydroxylating monooxygenase/peptidyl-hydroxyglycine alpha-amidating lyase (PHM/PAL)
Type: Family

In vertebrates, peptidylglycine alpha-amidating monooxygenase (PAM) is a multifunctional protein found in secretory granules. The protein contains two enzymes, peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL), that act sequentially to catalyse the alpha-amidation of neuroendocrine peptides :

peptidylglycine + ascorbate + O
2
= peptidyl-(2-hydroxyglycine) + dehydroascorbate + H
2
O

The product is unstable and dismutates to glyoxylate and the corresponding desglycine peptide amide. The first step of the reaction is catalysed by peptidylglycine alpha-hydroxylating monooxygenase (PHM), and is dependent on copper, ascorbate and molecular oxygen; peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) catalyses the second step of the reaction .
RNA polymerase, alpha subunit (RNA_pol_asu)
Type: Domain

RNA polymerases catalyse the DNA dependent polymerisation of RNA from DNA, using the four ribonucleoside triphosphates as substrates. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). Eukaryotic RNA polymerase I is essentially used to transcribe ribosomal RNA units, polymerase II is used for mRNA precursors, and III is used to transcribe 5S and tRNA genes. Each class of RNA polymerase is assembled from nine to fourteen different polypeptides. Members of the family include the largest subunit from eukaryotes; the gamma subunit from Cyanobacteria; the beta'
subunit from bacteria; the A' subunit from archaea; and the B'' subunit from chloroplast RNA polymerases.
G protein-coupled receptor 3/6/12 orphan (GPR_3/6/12_orphan)
Type: Family

Amongst the rhodopsin-like GPCRs are a family of orphan receptors whose members are designated GPR3, GPR6 and GPR12. Whilst these receptors do show sequence similarity to other rhodopsin-class GPCRs, the overall degree of similarity is very low, and evidence that they are functional GPCRs has not yet been gathered experimentally.
IgG-binding B (IgG-bd_B)
Type: Domain

This domain is found as a tandem repeat in Streptococcal cell surface proteins, such as the IgG binding proteins G. These proteins are type I membrane proteins that bind to the constant Fc region of IgG with high affinity.
Olfactory receptor (Olfact_rcpt)
Type: Family

The olfactory system is a highly specialised chemical recognition system that, like the immune system, is capable of discriminating with tremendous sensitivity between numerous foreign molecules in the environment. Olfactory transduction is believed to be initiated by the binding of odorants to specific receptor proteins in the cilia of olfactory receptor cells. Although little is known about the precise mechanism by which odorant binding might initiate membrane depolarisation, it is believed that cyclic AMP may serve as an intracellular messenger for olfactory transduction .

Olfactory receptors are integral membrane proteins that belong to the seven transmembrane (TM) rhodopsin-like G-protein coupled receptor family. Although the sequences of these proteins are very diverse, reflecting to some extent their broad range of activating ligands, nevertheless, motifs have been identified in the TM regions that are characteristic of virtually the entire superfamily . Amongst the exceptions are the olfactory receptors, which cluster together in a subfamily that lacks significant matches with TM domains 2, 4, and 6 .

Olfactory receptor genes form the largest known multigene family in the human genome . Each olfactory receptor can only interact with a subset of all potential odorants and a single odorant can activate multiple olfactory receptors, which enables a central neural logic of olfaction where the perception of smell arises from the combinatorial activity of multiple unique olfactory receptors that respond to an individual odorant . The structure of the human odorant receptor OR51E2 has been determined to be bound to the fatty acid propionate, which is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Therefore, it is suggested that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor .
Glycoside hydrolase, family 19, catalytic (Glyco_hydro_19_cat)
Type: Domain

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 19

comprises enzymes with only one known activity; chitinase (

).

Chitinases are enzymes that catalyse the hydrolysis of the beta-1,4-N-acetyl-D-glucosamine linkages in chitin polymers. Chitinases belong to glycoside hydrolase families 18 or 19 . Chitinases of family 19 (also known as classes I, II and IV) are enzymes from plants that function in the defence against fungal and insect pathogens by destroying their chitin-containing cell wall. Some family 19 chitinases are found in bacteria. Class I and II chitinases are similar in their catalytic domains. Class I chitinases have an N-terminal cysteine-rich, chitin-binding domain which is separated from the catalytic domain by a proline and glycine-rich hinge region. Class II chitinases lack both the chitin-binding domain and the hinge region. Class IV chitinases are similar to class I, but they are smaller in size due to certain deletions.

Despite any significant sequence homology with lysozymes, structural analysis reveals that family 19 chitinases, together with family 46 chitosanases, are similar to several lysozymes including those from T4-phage and from goose. The structures reveal that the different enzyme groups arose from a common ancestor glycohydrolase antecedent to the procaryotic/eucaryotic divergence .
Target SNARE coiled-coil homology domain (T_SNARE_dom)
Type: Domain

The process of vesicular fusion with target membranes depends on a set of SNAREs (SNAP-Receptors), which are associated with the fusing membranes . These proteins are classified as v-SNAREs and t-SNAREs based on their localisation on vesicle or target membrane while another classification scheme defines R-SNAREs and Q-SNAREs, as based on the conserved arginine or glutamine residue in the centre of the SNARE motif . Target SNAREs (t-SNAREs) are localised on the target membrane and belong to two different families, the syntaxin-like family and the SNAP-25 like family. One member of each family, together with a v-SNARE localised on the vesicular membrane, are required for fusion.

The N- and C-terminal coiled-coil domains of members of the SNAP-25 family and the most C-terminal coiled-coil domain of the syntaxin family are related to each other and form a new homology domain of approximately 60 amino acids. This domain is also found in other known proteins involved in vesicular membrane traffic, some of which belong to different protein families .
Proliferating cell nuclear antigen, PCNA (Pr_cel_nuc_antig)
Type: Family

Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein that plays a key role in the control of eukaryotic DNA replication . It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNA
replication . The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes . In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.

Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses.
Sterol-sensing domain (SSD)
Type: Domain

The sterol-sensing domain (SSD) is an around 180 residues long cluster of five membrane-spanning segments. The SSD domain is conserved across phyla and confers sensitivity to regulation by sterol. It 'senses' the presence of sterol substrates through interactions and may modulate protein behaviours with changing sterol levels. SSD is present in several membrane proteins that function in cholesterol metabolism, transport, and signalling. This domain is build around a conserved core that is essential for the sterol-dependent functions. Conformational changes of SSD are crucial for the sterol sensing and transport .

Based on their functions and structures, SSD-containing proteins were categorised into two types - moderator (M) class and transporter (T) class . Members in class M are Scap and HMGCR, both of which moderate the rate of sterol synthesis based on current sterol levels. Class T transporters, including NPC1, Ptch, and their homologs share a nearly identical transmembrane (TM) core with the bacterial multidrug-resistance transporters in the resistance/nodulation/division (RND) family. In class T, the conserved TM core consists of 12 TMs that fold into two repeats, named SSD and SSDL (SSD-like).

In addition to the proteins above, the SSD is also found in a number of bacterial drug resistance proteins.