SII-SWORD/CoKE huggingface dataset:
Sodium:neurotransmitter symporter, betaine (Na/ntran_symport_betaine)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

Cells regulate their volume and adapt to alterations in the tonicity of their local environment by adjusting their solute content accordingly. Resultant water movements rapidly establish osmotic balance. Solutes utilised in this manner are referred to as osmolytes and include: glycerophosphorylcholine, betaine, myo-inositol, sorbitol and taurine . Cell membrane transporters for betaine and taurine have been cloned, and by sequence similarity they have been shown to belong to the Na
+
and Cl
-
-coupled neurotransmitter transporter superfamily. Functional studies of the cloned betaine transporter (BGT-1) have revealed that it can also transport GABA, and that its mode of transport is electrogenic, with uptake of betaine depolarising the cell . In humans, the gene maps to chromosome 12p13, and is found to be expressed in: the kidney, brain, liver, heart, skeletal muscle and placenta.
Sodium:neurotransmitter symporter, creatine (Na/ntran_symport_creatine)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

A Na
+
and Cl
-
-coupled creatine transporter has been cloned from human and rodent tissues. Initially it was mistaken for a choline transporter . The creatine transporter species homologues are near identical (98% identity human vs. rat and rabbit) and they are most closely related to the transporters reported for taurine, GABA and betaine. Northern blot analysis of creatine transporter distribution reveals that the highest levels of mRNA expression are in: skeletal muscle, kidney and heart, with lower levels in brain and other tissues. Within the brain, the highest levels were detected in the cerebellum and hippocampus. This expression pattern correlates well with those tissues known to possess a high creatine uptake capacity .
Diaminopimelate decarboxylase, LysA (DAP_deCOOHase_LysA)
Type: Family

Pyridoxal-dependent decarboxylases that act on ornithine-, lysine-, arginine- and related substrates can be classified into different families on the basis of sequence similarity . One of these families includes ornithine decarboxylase (ODC), which catalyses the transformation of ornithine into putrescine; prokaryotic diaminopimelate decarboxylase, which catalyses the conversion of diaminopimelate into lysine; Pseudomonas syringae pv. tabaci protein, tabA, which is probably involved in tabtoxin biosynthesis and is similar to diaminopimelate decarboxylase; and bacterial and plant biosynthetic arginine decarboxylase, which catalyses the transformation of arginine into agmatine, the first step in putrescine synthesis from arginine.

Although these proteins, which are known collectively as group IV decarboxylases , probably share a common evolutionary origin, their levels of sequence similarity are low, being confined to a few short conserved regions. These conserved motifs suggest a common structural arrangement for positioning of substrate and the cofactor pyridoxal 5'-phosphate among bacterial diaminopimelate ddecarboxylases, eukaryotic ornithine decarboxylases and arginine decarboxylases .

This entry represents the diaminopimelate decarboxylase LysA, which converts meso-diaminopimelate into lysine and is the last step of the DAP lysine biosynthetic pathway. The structure of bacterial diaminopimelate decarboxylase has been determined .
Sodium/calcium exchanger, isoform 1 (NaCa_exhngr1)
Type: Family

Na
+
/Ca
2+
exchange proteins are involved in maintaining Ca
2+
homeostasis in a wide variety of cell types. They are found in both the plasma membrane and intracellular organellar membranes, where they exchange Na
+
for Ca
2+
in an electrogenic manner. When located in the plasma membrane, they generally utilise the transmembrane (TM) Na
+
concentration gradient in order to extrude Ca
2+
from cells. Three mammalian isoforms have been cloned to date (NCX1-3), which consist of 920-970 amino acid residues that are predicted to possess 11 or 12 TM domains. Interestingly, they possess a short motif (~30 residues) that is similar to the Na
+
/K
+
-ATPase, although its function is unknown .

NCX1 is the principal Na
+
/Ca
2+
exchanger of cardiac myocytes, where it is thought to play an important role in excitation-contraction coupling. It is also found in a variety of other tissues, suggesting it serves as a housekeeping protein, maintaining low cytosolic Ca
2+
concentration. Alternatively spliced variants of NCX1 have been identified, expression of which is cell type-specific. Sequence analysis reveals two sets of tandem repeats are found within the NCX1 protein sequence, which are usually referred to as alpha and beta. The alpha repeats are thought to be involved in the ion binding and translocation reactions of the exchanger, and the first beta repeat may be part of a regulatory site that responds to Ca
2+
concentration.
Protein G-related albumin-binding (GA) module (GA_module)
Type: Domain

Protein G-related albumin-binding (GA) modules occur on the surface of numerous Gram-positive bacterial pathogens. Protein G of group C and G Streptococci interacts with the constant region of IgG and with human serum albumin. The GA module is composed of a left-handed three-helix bundle and is found in a range of bacterial cell surface proteins . GA modules may promote bacterial growth and virulence in mammalian hosts by scavenging albumin-bound nutrients and camouflaging the bacteria. Variations in sequence give rise to differences in structure and function between GA modules in different proteins, which could alter pathogenesis and host specificity due to their varied affinities for different species of albumin . Proteins containing a GA module include PAB from Peptostreptococcus magnus .
Mycobacterial pentapeptide repeat (Mycobac_pentapep)
Type: Repeat

These repeats are found in many mycobacterial proteins. The repeats are most common in the PPE family of proteins, where they
are found in the MPTR (major polymorphic tandem repeat) subfamily. PPE10, one of the members, is important for capsular integrity and virulence, although the function of these repeats is unknown . The repeat can be approximately described as XNXGX, where X can be any amino acid. These repeats are similar to A(D/N)LXX pentapeptide repeats , however it is not clear if these two families are structurally related.
Ornithine decarboxylase antizyme (ODC_AZ)
Type: Family

Ornithine decarboxylase antizyme (ODC-AZ) binds to, and destabilises, ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis. ODC is then rapidly degraded. The expression of ODC-AZ requires programmed, ribosomal frameshifting which is modulated according to the cellular concentration of polyamines. High levels of polyamines induce a +1 ribosomal frameshift in the translation of mRNA for the antizyme leading to the expression of a full-length protein. At least two forms of ODC-AZ in mammals and one homologue in Drosophila (protein Gutfeeling) have been identified.
Surfeit locus 1/Shy1 (Surf1/Shy1)
Type: Family

This entry includes SURF1 and Shy1 proteins. The surfeit locus 1 gene (SURF1 or surf-1) encodes a conserved protein of about 300 amino-acid residues that seems to be involved in the biogenesis of cytochrome c oxidase . Vertebrate SURF1 is evolutionary related to yeast protein Shy1, which is a mitochondrial inner membrane protein required for assembly of cytochrome c oxidase . There seems to be two transmembrane regions in these proteins, one in the N-terminal, the other in the C-terminal.

Defects in SURF1 are a cause of Leigh syndrome (LS). LS is a severe neurological disorder characterised by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency .
Surfeit locus 4 (Surf4)
Type: Family

The surfeit locus gene SURF4 (or surf-4) encodes a conserved integral eukaryotic membrane protein of about 270 to 300 amino-acid residues that seems to be located in the endoplasmic reticulum .
Tudor domain (Tudor)
Type: Domain

The drosophila Tudor protein, the founder of the Tudor domain family, is encoded by a 'posterior group' gene, which when mutated disrupt normal abdominal segmentation and pole cell formation. Another drosophila gene, homeless, is required for RNA localization during oogenesis. The tudor protein contains multiple repeats of a domain which is also found in homeless .

The tudor domain is found in many proteins that colocalise with ribonucleoprotein or single-strand DNA-associated complexes in the nucleus, in the mitochondrial membrane, or at kinetochores. At first it was not clear if the domain binds directly to RNA and ssDNA, or controls interactions with the nucleoprotein complexes but it is now known that this domain recognises and binds to methyl-arginine-lysine residues, playing important roles in diverse epigenetics, gene expression and the regulation of various small RNAs . The tudor-containing protein homeless, also contains a zinc finger typical of RNA-binding proteins .

This domain has been implicated in protein-protein interactions in which methylated protein substrates bind to these domains. One example is the Tudor domain of Survival of Motor Neuron (SMN), linked to spinal muscular atrophy, which binds to symmetrically dimethylated arginines of arginine-glycine (RG) rich sequences found in the C-terminal tails of Sm proteins. The resolution of the solution structure of the Tudor domain of human SMN revealed that the Tudor domain forms a strongly bent antiparallel β-sheet with five strands forming a barrel-like fold. The structure exhibits a conserved negatively charged surface that interacts with the C-terminal Arg and Gly-rich tails of the spliceosomal Sm D1 and D3 proteins .
Sirtuin family (Sirtuin)
Type: Family

The sirtuin (also known as Sir2) family is broadly conserved from bacteria to human. Yeast Sir2 (silent mating-type information regulation 2),
the founding member, was first isolated as part of the SIR complex required for maintaining a modified chromatin structure at telomeres. Sir2 functions
in transcriptional silencing, cell cycle progression, and chromosome stability . Although most sirtuins in eukaryotic cells are located in the nucleus, others are cytoplasmic or mitochondrial.

This family is divided into five classes (I-IV and U) on the basis of a phylogenetic analysis of 60 sirtuins from a wide array of organisms . Class I and class IV are further divided into three and two subgroups, respectively. The U-class sirtuins are found only in Gram-positive bacteria . The S. cerevisiae genome encodes five sirtuins, Sir2 and four additional proteins termed 'homologues of sir two' (Hst1p-Hst4p) . The human genome encodes seven sirtuins, with representatives from classes I-IV .

Sirtuins are responsible for a newly classified chemical reaction, NAD-dependent protein deacetylation. The final products of the reaction are the
deacetylated peptide and an acetyl ADP-ribose . In nuclear sirtuins this deacetylation reaction is mainly directed against histones acetylated lysines .

Sirtuins typically consist of two optional and highly variable N- and C-terminal domain (50-300 aa) and a conserved catalytic core domain (~250 aa). Mutagenesis experiments suggest that the N- and C-terminal regions help direct catalytic core domain to different targets .

The 3D-structure of an archaeal sirtuin in complex with NAD reveals that the protein consists of a large domain having a Rossmann fold and a small domain containing a three-stranded zinc ribbon motif. NAD is bound in a pocket between the two domains .
GspF/PilC family (GspF/PilC)
Type: Family

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 secretion system 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 .
Amphiphysin (Amphiphysin)
Type: Family

Amphiphysins belong to the expanding BAR (Bin-Amphiphysin-Rvsp) family proteins, all members of which share a highly conserved N-terminal BAR domain, which has predicted coiled-coil structures required for amphiphysin dimerisation and plasma membrane interaction . Almost all members also share a conserved C-terminal Src homology 3 (SH3) domain, which mediates their interactions with the GTPase dynamin and the inositol-5'-phosphatase synaptojanin 1 in vertebrates and with actin in yeast. The central region of all these proteins is most variable. In mammals, the central region of amphiphysin I and amphiphysin IIa contains a proline-arginine-rich region for endophilin binding and a CLAP domain, for binding to clathrin and AP-2. The interactions mediated by both the central and C-terminal domains are believed to be modulated by protein phosphorylation .

Amphiphysins are key players in the control of plasma membrane curvature, membrane shaping and membrane remodeling, involved involved in clathrin-mediated endocytosis, the endosomal sorting of membrane proteins, actin function, and signalling pathways . In vertebrates, amphiphysins may regulate, but are not essential for clathrin-mediated endocytosis of SVs. However, in Drosophila amphiphysin is not involved at all in SV endocytosis but is required for T-tubule structure and excitation-contraction coupling muscles and plays a role in membrane morphogenesis in developing photoreceptors and a variety of other cells .
Immunoglobulin/major histocompatibility complex, conserved site (Ig/MHC_CS)
Type: Conserved_site

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .

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

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Lutheran blood group glycoprotein (B-CAM cell surface glycoprotein) (Auberger B antigen) (F8/G253 antigen) belongs to the Lutheran blood group system and is associated with Lu(a/b), Au(a/b), LU6 to LU20 antigens.
Tubulin/FtsZ, GTPase domain (Tubulin_FtsZ_GTPase)
Type: Domain

This entry represents a GTPase domain found in all tubulin chains, such as tubulin alpha, beta and gamma chains, plant ARC3 and prokaryotic FtsZ and CetZ proteins . These proteins are involved in polymer formation. Tubulin is the major component of microtubules, while FtsZ (homologue of eukaryotic tubulin) is the polymer-forming protein of bacterial cell division, it is part of a ring in the middle of the dividing cell that is required for constriction of cell membrane and cell envelope to yield two daughter cells . FtsZ can polymerise into tubes, sheets, and rings in vitro and is ubiquitous in bacteria and archaea. CetZ co-exists with FtsZ in many archaea. Cetz does not affect cell division, instead, it is involved in cell shape control . Arabidopsis chloroplast protein ARC3 (At1g75010) is a Z-ring accessory protein involved in the initiation of plastid division and division site placement .
Carbon-nitrogen hydrolase (C-N_Hydrolase)
Type: Domain

The carbon-nitrogen hydrolase domain is an around 265-residue domain found in numerous enzymes involved in the reduction of organic nitrogen compounds and ammonia production. Based on their sequence similarity and on the reactions
they catalyse, these enzymes can be classified into functionally distinct groups including :

Nitrilases (

), which cleave various nitriles into the corresponding acids and ammonia.

Cyanide hydratase (

) of pathogenic fungi, which detoxifies HCN that is released by their hosts, cyanogenic plants, after injury.

Aliphatic amidases (

), which enable prokaryotes to use acetamides as both carbon and nitrogen source.

Beta-ureidopropionase (also known as beta-alanine synthase or N-carbamoyl-beta-alanine amino hydrolase;

), which catalyses the last step of pyrimidine catabolism.

Glutamine-dependent NAD(+) synthetase (also known as AdgA, for ammonia-dependent growth) from Rhodobacter species (

). It appears to be essential for using various amino acids as nitrogen sources.

Biotinidase (

), which catalyses the hydrolysis of biocytin to biotin and lysine.

Pantetheinase (

) (Pantetheine hydrolase) (Vanin), which hydrolyzes specifically one of the carboamide linkages in D-pantetheine, thus recycling pantothenic acid (vitamin B5) and releasing cysteamine.

Apolipoprotein N-acyltransferase ([ec:2.3.1.-]) (gene lnt), a bacterial enzyme that transfers the fatty acyl group on membrane lipoproteins.

Glutamine-dependent NAD(+) synthetase (

), which catalyses the final step in NAD+ synthesis .

The carbon-nitrogen hydrolase domain is characterised by several conserved motifs, one of which contains a cysteine that is part of the catalytic site in nitrilases. Another highly conserved motif includes a glutamic acid that might also be involved in catalysis .
Cell cycle checkpoint protein, Rad1 (Cell_cycle_checkpoint_Rad1)
Type: Family

Rad1 is a component of the 9-1-1 cell-cycle checkpoint response complex, which plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress . The 9-1-1 complex is recruited to DNA lesions upon damage by the Rad17 (Rad24 in budding yeast)-replication factor C (RFC) clamp loader complex. The 9-1-1 complex is necessary for the recruitment of C12orf32/RHINO to sites of double-stranded breaks (DSB) occurring during the S phase . Rad1 isoform 1 possesses 3'->5' double stranded DNA exonuclease activity .

In Caenorhabditis elegans, the cell cycle checkpoint protein RAD1 homologue mrt-2 has a role in genome stability by promoting DNA double strand break-induced cell cycle arrest and apoptosis, and is required for maintaining telomere length and germline immortality .
2-oxo acid dehydrogenase, lipoyl-binding site (2-oxoA_DH_lipoyl-BS)
Type: Binding_site

The 2-oxo acid dehydrogenase multienzyme complexes from bacterial and eukaryotic sources catalyse the oxidative decarboxylation of 2-oxo acids to the corresponding acyl-CoA. These include:

Pyruvate dehydrogenase complex (PDC).

2-oxoglutarate dehydrogenase complex (OGDC).

Branched-chain 2-oxo acid dehydrogenase complex (BCOADC).

These three complexes share a common architecture: they are composed of multiple copies of three component enzymes - E1, E2 and E3. E1 is a thiamine pyrophosphate-dependent 2-oxo acid dehydrogenase, E2 a dihydrolipamide acyltransferase, and E3 an FAD-containing dihydrolipamide dehydrogenase.