SII-SWORD/CoKE huggingface dataset:
Chromogranin A/B/C (Granin)
Type: Family

Granins (chromogranins or secretogranins) are a family of acidic proteins present in the secretory granules of a wide variety of endocrine and neuro-endocrine cells. The exact function(s) of these proteins is not yet known but they seem to be the precursors of biologically active peptides and/or they may act as helper proteins in the packaging of peptide hormones and neuropeptides. Apart from their subcellular location and the abundance of acidic residues (Asp and Glu), these proteins do not share many structural similarities. Only one short region, located in the C-terminal section, is conserved in all these proteins, such as:

Chromogranin A (CGA): CGA is a protein of about 420 residues; it is the precursor of the peptide pancreastatin which strongly inhibits glucose- induced insulin release from the pancreas.

Secretogranin 1 (chromogranin B): A sulfated protein of about 600 residues.

Secretogranin 2 (chromogranin C): A sulfated protein of about 650 residues.

Chromogranins and secretogranins together share a C-terminal motif, whereas chromogranins A and B share a region of high similarity in their N-terminal section; this region includes two cysteine residues involved in a disulphide bond.
Sodium:dicarboxylate symporter (Na-dicarboxylate_symporter)
Type: Family

It has been shown that integral membrane proteins that mediate the uptake of a wide variety of molecules with the concomitant uptake of sodium ions (sodium symporters) can be grouped, on the basis of sequence and functional similarities into a number of distinct families. One of these families is known as the sodium:dicarboxylate symporter family (SDF) .

Such re-uptake of neurotransmitters from the synapses, is thought to be an important mechanism for terminating their action, by removing these chemicals from the synaptic cleft, and transporting them into presynaptic nerve terminals, and surrounding neuroglia. This removal is also believed to prevent them accumulating to the point of reaching neurotoxic .

The structure of these transporter proteins has been variously reported to contain from 8 to 10 transmembrane (TM) regions, although 10 now seems to be the accepted value.

Members of the family include: several mammalian excitatory amino acid transporters, and a number of bacterial transporters. They vary with regards to their dependence on transport of sodium, and other ions.
T2SS_GspF/T4SS_PilC conserved site (T2SS_GspF/T4SS_PilC_CS)
Type: Conserved_site

GspF is the inner membrane component of the type II secretion system (T2SS). It interacts with GspE, a cytoplasmic hexameric ATPase of the T2SS . It shows considerable sequence similarity to PilC, which is required for the formation of type IV pili .

The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space . T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK . GspD has been shown to interact with the inner membrane component GspC .
Phosphotransferase system, IIB component, type 1 (PTS_IIB_1)
Type: Domain

This entry represents the component IIB of the glucose family of PTS systems (type 1).

Several PTS permease families are currently recognised, namely, the (i) glucose (including glucoside), (ii) fructose (including mannitol), (iii) lactose (including N,N-diacetylchitobiose), (iv) galactitol, (v) glucitol, (vi) mannose, and (vii) l-ascorbate families .

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to enzyme-I (EI) of PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease which consists of at least three structurally distinct domains (IIA, IIB, and IIC) which can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).

The first domain (IIA) carries the first permease-specific phoshorylation site, a histidine, which is phosphorylated by phospho-HPr. The second domain (IIB) is phosphorylated by phospho-IIA on a cysteinyl or histidyl residue, depending on the permease. Finally, the phosphoryl group is transferred from the IIB domain to the sugar substrate in a process catalyzed by the IIC domain; this process is coupled to the transmembrane transport of the sugar.
Calponin/LIMCH1 (Calponin/LIMCH1)
Type: Family

Calponin is a smooth muscle-specific, actin-, tropomyosin- and calmodulin-binding protein believed to be involved in regulation or modulation of contraction . Interaction of the protein with actin inhibits actomyosin MgATPase activity. Multiple isoforms are found in smooth muscle . Calponin is a basic protein of ~34kDa . The protein contains three repeats of a well-conserved 26-residue domain (see

).

This entry also includes LIM and calponin homology domains-containing protein 1 (LIMCH1), which contains a LIM zinc-binding domain and a CH (calponin-homology) domain.
Xylose isomerase (Xylose_isomerase)
Type: Family

Xylose isomerase (

) is an enzyme found in microorganisms which catalyzes the interconversion of D-xylose to D-xylulose. It can also isomerize D-ribose to D-ribulose and D-glucose to D-fructose. The enzyme is a homotetramer, which is stabilised by cobalt, and requires magnesium for its catalytic activity. Each subunit contains 2 domains: the core domain is a parallel α-β barrel; the C-terminal domain is a loop structure consisting of 5 helices and is involved in intermolecular contacts between adjacent subunits . The active site lies in a deep pocket near the C-terminal ends of the strands of the barrel domain and includes residues from a second subunit. The tetramer is effectively a dimer of "active" dimers, the active sites being composed of residues from both subunits .

Xylose isomerase also exists in plants where it is homodimeric and is manganese-dependent.
Osteonectin-like, conserved site (Osteonectin_CS)
Type: Conserved_site

The osteonectin like domain, of unknown function, is found in extracellular proteins strongly expressed in tissues undergoing morphogenesis. It is a 240 amino acids domain, highly conserved, localised in the C-terminal part of the protein .

This domain has a N-terminal section of about 90 residues that contains 11 conserved cysteines, a central section that is probably in an α-helical conformation, and a C-terminal section that contains two EF-hand type calcium-binding regions and three conserved cysteines. This topology is schematically represented below.

+----+
| |
xCxCxCxxCCxCxxxCxxCxCxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx(Ca)xCxxC(Ca)Cxx

C: conserved cysteines involved in disulphide bonds.
Ca: EF-hand region see(

).
Lysosome-associated membrane glycoprotein (Lysosome-assoc_membr_glycop)
Type: Family

Lysosome-associated membrane glycoproteins (lamp) are integral membrane proteins, specific to lysosomes, and whose exact biological function is not yet clear. Structurally, the lamp proteins consist of two internally homologous lysosome-luminal domains separated by a proline-rich hinge region; at the C-terminal extremity there is a transmembrane region (TM) followed by a very short cytoplasmic tail (C). In each of the duplicated domains, there are two conserved disulphide bonds. This structure is schematically represented in the figure below.

+-----+ +-----+ +-----+ +-----+
| | | | | | | |
xCxxxxxCxxxxxxxxxxxxCxxxxxCxxxxxxxxxCxxxxxCxxxxxxxxxxxxCxxxxxCxxxxxxxx
+--------------------------++Hinge++--------------------------++TM++C+

In mammals, there are two closely related types of lamp: lamp-1 and lamp-2, which form major components of the lysosome membrane. In chicken lamp-1 is known as LEP100.

Also included in this entry is the macrophage protein CD68 (or macrosialin) is a heavily glycosylated integral membrane protein whose structure consists of a mucin-like domain followed by a proline-rich hinge; a single lamp-like domain; a transmembrane region and a short cytoplasmic tail.
GPCR, family 2, diuretic hormone receptor (GPCR_2_diuretic_rcpt)
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 secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

Insect diuretic hormones regulate fluid and ion secretion, and the receptors with which they interact are attractive targets for new insect control agents . Diuretic hormone receptors from the moth, Manduca sexta, and the house cricket, Acheta domesticus, share 53% sequence identity and have been shown to be members of the secretin-like family of GPCRs . The receptors bind diuretic hormone with high affinity and stimulate adenylate cyclase with high potency.
Octopamine receptor (Octopmn_rcpt)
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 .

The insect octopamine receptor mediates the attenuation of adenylate cyclase activity. Sequence and pharmacological comparisons indicate that the octopamine receptor is unique, but closely related to mammalian adrenergic receptors, perhaps as an evolutionary precursor .
Gas vesicle protein GvpC (Gas-vesicle_GvpC)
Type: Repeat

Gas vesicles are small, hollow, gas filled protein structures found in several cyanobacterial and archaebacterial microorganisms . They allow the positioning of the bacteria at the favorable depth for growth. Gas vesicles are hollow cylindrical tubes, closed by a hollow, conical cap at each end. Both the conical end caps and central cylinder are made up of 4-5 nm wide ribs that run at right angles to the long axis of the structure. Gas vesicles seem to be constituted of two different protein components: GVPa and GVPc. GVPc is a minor constituent of gas vesicles and seems to be located on the outer surface. Structurally, cyanobacterial GVPc consists of four or five tandem repeats of a 33 residue sequence flanked by sequences of 18 and 10 residues at the N- and C-termini, respectively.
Polyadenylate-binding protein/Hyperplastic disc protein, C-terminal (PABP_HYD_C)
Type: Domain

The polyadenylate-binding protein (PABP) has a conserved C-terminal domain (PABC), which is also found in the hyperplastic discs protein (HYD) family of ubiquitin ligases that contain HECT domains (

) . PABP recognises the 3' mRNA poly(A) tail and plays an essential role in eukaryotic translation initiation and mRNA stabilisation/degradation. PABC domains of PABP are peptide-binding domains that mediate PABP homo-oligomerisation and protein-protein interactions. In mammals, the PABC domain of PABP functions to recruit several different translation factors to the mRNA poly(A) tail .
Hepatitis core antigen (Hepatitis_core)
Type: Family

This entry represent the core antigen of the viral capsid (HBcAg) from various Hepatitis B virus (HBV), which is a major human pathogen. The virus is composed of an outer envelope of host-derived lipid containing the surface proteins, and an inner protein capsid that contains genomic DNA. The capsid is composed of a single polypeptide, HBcAg, also known as the core antigen. The capsid has a 5-helical fold, where two long helices form a hairpin that dimerises into a 4-helical bundle ; this fold is unusual for icosahedral viruses. The monomer fold is stabilised by a hydrophobic core that is highly conserved among human viral variants. The capsid is assembled from dimers via interactions involving a highly conserved arginine-rich region near the C terminus. This viral capsid acts as a core antigen, the major immunodominant region lying at the tips of the α-helical hairpins that form spikes on the capsid surface.
DNA polymerase family X, beta-like (DNA_pol_X_beta-like)
Type: Family

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-β secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. Members of family X are small (about 40kDa) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as yeast pol 4), and terminal deoxynucleotidyl-transferase (TdT) (

). The former functions in DNA repair, while the latter terminally adds single nucleotides to polydeoxynucleotide chains. Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.
Type III secretion system inner membrane R protein (T3SS_IM_R)
Type: Family

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior . There have been four secretion systems described in animal enteropathogens such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .
Gonadotropin-releasing hormone (GnRH)
Type: Conserved_site

The gonadotropin-releasing hormones (GnRH) (gonadoliberin) are a family of peptides that play a pivotal role in reproduction. The main function of GnRH is to act on the pituitary to stimulate the synthesis and secretion of luteinizing and follicle-stimulating hormones, but GnRH also acts on the brain, retina, sympathetic nervous system, gonads and placenta in certain species. There seems to be at least three forms of GnRH . The second form is expressed in midbrain and seems to be widespread. The third form has only been found so far in fish. GnRH is a C-terminal amidated decapeptide processed from a larger precursor protein. Four of the ten residues are perfectly conserved in all species where GnRH has been sequenced.
SAC domain (SAC_dom)
Type: Domain

The Sac domain is a region of homology between the N terminus of synaptojanin and the otherwise unrelated yeast protein Sac1p. The Sac domain is approximately 400 residues in length, and proteins containing this domain show approximately 35% identity with other Sac domains throughout this region. The Sac domain exhibits phosphatidylinositol polyphosphate phosphatase activity and can hydrolyse phosphate from any of the three positions of inositol that may be phosphorylated (3-, 4-and 5). However, adjacent phosphates are resistant to hydrolysis. Sac domains cannot hydrolyse phosphate from phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), or PtdIns(3,4)P2, or PtdIns(3,4,5)P3, but can hydrolyse PtdIns(3,5)P2 .

The Sac domain consists of seven highly conserved motifs which appear to define the catalytic and regulatory regions of the phosphatase. The sixth conserved region contains a highly conserved C-x(5)-R-[TS] motif, thought to be the catalytic motif of many metal-independent protein and inositide polyphosphate phosphatases. Interestingly, the Inp51p Sac domain in which the cysteine, arginine and threonine/serine residues within the C-x(5)-R-[TS] motif are absent, does not exhibit any phosphatase activity .

Two classes of Sac domain proteins have been identified in mammals as well as lower eukaryotes . The first comprises proteins, which, in addition to an N-terminal phosphatase Sac domain, have all the domains associated with type II phosphatidylinositol phosphate 5-phosphatases:

Mammalian synaptojanins, type II phosphatidylinositol phosphate 5-phosphatases.

Yeast INP51, a 108kDa membrane protein. It is involved in endocytosis and regulation of the actin cytoskeleton under conditions of normal vegetative growth. Although the Sac phosphatase domain of INP51 may be catalytically inactive, the domain may retain other functions.

Yeast INP52, a 133kDa membrane protein. It is involved in endocytosis and regulation of the actin cytoskeleton under conditions of normal vegetative growth.

Yeast INP53, a 124kDa membrane protein. It appears to have a role in intra-Golgi and Golgi-to-endosomal trafficking.

The other class of Sac-containing phosphatases consists of proteins with an N-terminal Sac phosphatase domain and no other recognizable domains:

Yeast Sac1p, a 67kDa membrane protein found in the endoplasmic reticulum (ER) and Golgi. It regulates the actin cytoskeleton and phospholipid metabolism.

Yeast FIG4, a 101kDa protein encoded by a pheromone regulated or induced gene. FIG4 might function to regulate effector molecules of the actin cytoskeleton during mating.
VHS domain (VHS_dom)
Type: Domain

The VHS domain is an about 150 residues long domain, whose name is derived from its occurrence in VPS-27, Hrs and STAM. The VHS domain is found at the N- termini of proteins associated with endocytocis and/or vesicular trafficking, often in association with other domains like FYVE, SH3 or TAM . The VHS domain of Hrs makes both intra- and intermolecular interactions with FYVE domains and it has been proposed that it might as well interact with other domains. The VHS domain might function as a multipurpose docking adapter that localizes proteins to the membrane through interactions with the membrane and/or the endocytic machinery .

Resolution of the crystal structure of the VHS domain of Drosophila Hrs and human Tom1 revealed that it consists of eight helices arranged in a superhelix .
Proteasome/cyclosome repeat (Proteasome/cyclosome_rpt)
Type: Repeat

A weakly conserved repeat module of unknown function, which occurs in two regulatory subunits of the 26S-proteasome and in one subunit of the anaphase-promoting complex .
Spectrin repeat (Spectrin_repeat)
Type: Repeat

Spectrin repeats are found in several proteins involved in cytoskeletal structure and in proteins with a more regulatory role mostly in animals . This entry includes spectrin alpha and beta subunits, alpha-actinin and dystrophin .
Carboxylesterase, type B (CarbesteraseB)
Type: Domain

Higher eukaryotes have many distinct esterases. Among the different types are those which act on carboxylic esters (

). Carboxyl-esterases have been classified into three categories (A, B and C) on the basis of differential patterns of inhibition by organophosphates. The sequence of a number of type-B carboxylesterases indicates that the majority are evolutionary related. As is the case for lipases and serine proteases, the catalytic apparatus of esterases involves three residues (catalytic triad): a serine, a glutamate or aspartate and a histidine.