SII-SWORD/CoKE huggingface dataset:
Amphiphysin, isoform 1 (Amphiphysin_1)
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 proteins involved in clathrin-mediated endocytosis clathrin-mediated endocytosis, actin function, and signalling pathways .

Amphiphysin 1 was first identified in 1992 as a brain protein that was partially-associated with synaptic vesicles. Following its cloning, it was also realised to be a human auto-antigen that is detected in a rare neurological disease, Stiff-Man Syndrome, and also in certain types of cancer . Amphiphysin 1 senses and facilitates membrane curvature to mediate synaptic vesicles invagination and fission during newly retrieved presynaptic vesicle formation and also acts as a linker protein binding with dynamin, clathrin, Amphiphysin II, and other dephosphins in the clathrin-coated complex. Amphiphysin 1 is cleaved an asparagine endopeptidase (AEP), which generates a fragment that increases with aging. This fragment disrupts the normal endocytic function of Amphiphysin 1, leading to synaptic dysfunction, as it activates CDK5 inducing tau hyperphosphorylation. Therefore, Amphiphysin 1 posttranslational modification contributes to pathogenesis of Alzheimer's disease, being the AEP a therapeutic target .
GAF domain (GAF)
Type: Domain

The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in guanylyl cyclases and phytochromes . The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain . Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively, these products up-regulating catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding. Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region .

The GAF domain is also found in FhlA (formate hydrogen lyase transcriptional activator) and NifA, a transcriptional activator required for activation of most Nif operons, which are directly involved in nitrogen fixation. NifA interacts with sigma-54 .
Bicarbonate transporter, eukaryotic (HCO3_transpt_euk)
Type: Family

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.
Rad1/Rec1/Rad17 (Rad1_Rec1_Rad17)
Type: Family

This family consists of the repair proteins Rad1, Rec1 and Rad17.

Rad1 is a component of the 9-1-1 cell-cycle checkpoint response complex (Rad9-Rad1-Hus1) that plays a major role in DNA repair . Rad1 isoform 1 possesses 3'->5' double stranded DNA exonuclease activity .

Rec1 of Ustilago maydis plays a key role in regulating the genetic system of this fungus. Rec1 mutants are very sensitive to UV light. Mutation leads to a complex phenotype with alterations in DNA repair, recombination, mutagenesis, meiosis and cell division . Rec1 shows 3'--5' exonuclease activity, but only in cells over-expressing Rec1.
Transcription factor Otx2 (Otx2_TF)
Type: Family

Otx proteins constitute a class of vertebrate homeodomain-containing transcription factors that have been shown to be essential for anterior head formation, including brain morphogenesis. They are orthologous to the product of the Drosophila head gap gene, orthodenticle (Otd), and appear to play similar roles in both, since the developmental abnormalities caused by disruption of these transcription factors in one, can be recovered by substitution of the factor(s) from the other. Such studies have provided strong evidence that there exists a conserved genetic programme for insect and mammalian brain development, which presumably arose in a more primitive common ancestor .

Two vertebrate orthodenticle-related transcription factors have been indentified, Otx1 and Otx2, which have sizes of 355 and 289 residues respectively. They contain a bicoid-like homeodomain, which features a conserved lysine residue at position 9 of the DNA recognition helix, which is thought to confer high-affinity binding to TAATCC/T elements on DNA . Otd-like transcription factors have also been found in zebrafish and certain lamprey species.
Amphiphysin 2 (Amphiphysin_2)
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 proteins that are thought to be involved in clathrin-mediated endocytosis, 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 .

This entry includes amphiphysin 2 (also known as Myc box-dependent-interacting protein 1) , which was the second amphiphysin family member found in mammals. The gene encoding it has been found to be alternatively spliced. The various products have been named: BIN-1, Sh3P9, BRAMP-2 and ALP-1. They have different distribution patterns, with the largest form (~95 kD) being expressed solely in the brain, where it shares a very similar (if not identical) distribution pattern to amphiphysin 1 . This protein is a a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling. It is required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling . It is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production . It has been shown that in vitro, it has actin bundling activity and stabilizes actin filaments against depolymerization .
Sodium bicarbonate cotransporter (Na/HCO3_transpt)
Type: Family

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

Na
+
/HCO
3
-
co-transport proteins are involved in cellular HCO
3
-
absorption and secretion, and also with intracellular pH regulation. They mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes in most of the cell types so far investigated. A single HCO
3
-
is transported together with one to three Na
+
; this transport mode is therefore often electrogenic. In the kidney, an electrogenic Na
+
/HCO
3
-
co-transporter is the principal HCO
3
-
transporter of the renal proximal tubule, and is responsible for reabsorption of more than 85% of the filtered load of HCO
3
-
. Until recently, the molecular nature of these Na
+
/HCO
3
-
co-transporters had remained undiscovered, as initial attempts to clone them based on presumed homology to Cl
-
/HCO
3
-
(anion) exchangers had proved unsuccessful. Instead, an expression cloning strategy was successfully utilised to identify the Na
+
/HCO
3
-
co-transporter from salamander kidney, an organ previously found to possess electrogenic Na
+
/HCO
3
-
co-transport activity . At least 3 mammalian Na
+
/HCO
3
-
co-transporters have since been cloned, with similar primary sequence lengths and putative membrance topologies. One of these has been found to be a kidney-specific isoform , which is near-identical (except for a varying N-terminal region) to a more widely-distributed co-transporter cloned from pancreatic tissue .
Transcription factor Otx (Otx_TF)
Type: Family

Otx proteins constitute a class of vertebrate homeodomain-containing transcription factors that have been shown to be essential for anterior head formation, including brain morphogenesis. They are orthologous to the product of the Drosophila head gap gene, orthodenticle (Otd), and appear to play similar roles in both, since the developmental abnormalities caused by disruption of these transcription factors in one, can be recovered by substitution of the factor(s) from the other. Such studies have provided strong evidence that there exists a conserved genetic programme for insect and mammalian brain development, which presumably arose in a more primitive common ancestor .

Two vertebrate orthodenticle-related transcription factors have been indentified, Otx1 and Otx2, which have sizes of 355 and 289 residues respectively. They contain a bicoid-like homeodomain, which features a conserved lysine residue at position 9 of the DNA recognition helix, which is thought to confer high-affinity binding to TAATCC/T elements on DNA . Otd-like transcription factors have also been found in zebrafish and certain lamprey species.
Transcription factor Otx1 (Otx1_TF)
Type: Family

Otx proteins constitute a class of vertebrate homeodomain-containing transcription factors that have been shown to be essential for anterior head formation, including brain morphogenesis. They are orthologous to the product of the Drosophila head gap gene, orthodenticle (Otd), and appear to play similar roles in both, since the developmental abnormalities caused by disruption of these transcription factors in one, can be recovered by substitution of the factor(s) from the other. Such studies have provided strong evidence that there exists a conserved genetic programme for insect and mammalian brain development, which presumably arose in a more primitive common ancestor .

Two vertebrate orthodenticle-related transcription factors have been indentified, Otx1 and Otx2, which have sizes of 355 and 289 residues respectively. They contain a bicoid-like homeodomain, which features a conserved lysine residue at position 9 of the DNA recognition helix, which is thought to confer high-affinity binding to TAATCC/T elements on DNA . Otd-like transcription factors have also been found in zebrafish and certain lamprey species. Studies of mice lacking Otx1 (due to targeted gene disruption) have shed light on its role in development, such mice showing impaired corticogenesis and sense organ development. Phenotypic abnormalities noted in the cerebral cortices include reduced cell proliferation and total cell number, together with disruption of the formation of the normally well-ordered cortical cell layers, which are characteristic of these structures. Abnormalities are also observed in the eye and inner ear.
Exonuclease Rec1, Ustilaginaceae (Rec1_exonuc_Ustilaginaceae)
Type: Family

Rec1 of Ustilago maydis is a homologue of S. pombe Rad1 and S. cerevisiae Rad17 proteins. It plays a key role in regulating the genetic system of the fungus. Rec1 mutants are very sensitive to UV light - mutation leads to a complex phenotype with alterations in DNA repair, recombination, mutagenesis, meiosis and cell division. The predicted product of the REC1 gene is a polypeptide of 522 amino acid residues with molecular mass 57 kD. The protein shows 3'--5' exonuclease activity, but only in cells over-expressing Rec1. While it is distinguishable from the major bacterial nucleases, the protein has certain enzymatic features in common with epsilon, the proof-reading exonuclease subunit of Escherichia coli DNA polymerase III holoenzyme .
Sodium:neurotransmitter symporter, glycine, type 1 (Na/ntran_symport_glycine_GLY1)
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 .

Glycine is known to serve two contrasting roles as a neurotransmitter in the central nervous system. Firstly, it serves as an inhibitory neurotransmitter in the spinal cord, brainstem and retina, where it activates a ligand-gated Cl
-
channel. Secondly, it is an obligatory co-agonist for activation of the N-methyl-D-aspartate (NMDA) receptor - unless glycine is also bound to the NMDA receptor, glutamate cannot activate this ion channel. Not surprisingly, then, plasma membranes possess glycine transporters in order to regulate its concentration. Two independent genes have been identified that encode Na
+
and Cl
-
-coupled glycine transporters. Their products, referred to as GLYT-1 and GLYT-2, have differing distribution patterns within the central nervous system, suggesting they may subserve unique functions . Indeed the distribution of the GLYT-1 transporter suggests it may play a role in regulating glycine concentrations in brain regions containing glycine-dependent NMDA receptors . Three different mRNA isoforms for GLYT-1 have been detected. These arise as a result of differential splicing, or the usage of multiple promoter sites. They encode transporters of 633, 638 and 692 amino acid residues, all three having 50-60% similarity to other transporters in the Na
+
and Cl
-
-coupled neurotransmitter transporter superfamily.
S1 domain (S1_domain)
Type: Domain

The S1 domain was originally identified in ribosomal protein S1 but is found in a large number of proteins involved in RNA metabolism. It belongs to the OB-fold family. The structure of the S1 RNA-binding domain from the Escherichia coli polynucleotide phosphorylase has been determined using NMR methods and consists of a five-stranded antiparallel β barrel. Conserved residues on one face of the barrel and adjacent loops form the putative RNA-binding site .

The structure of the S1 domain is very similar to that of cold shock proteins. This suggests that they may both be derived from an ancient nucleic acid-binding protein .

This entry does not include translation initiation factor IF-1 S1 domains.
Ryanodine receptor Ryr (Ryanodine_rcpt)
Type: Domain

This domain is called RyR for Ryanodine receptor . The domain is found in four copies in the ryanodine receptor. A single copy of this domain encodes an unknown protein from Bacteroides thetaiotamicron, and and suggests that the repeats in RyRs may have a prokaryotic origin . The function of this domain is unknown.
SCP2 sterol-binding domain (SCP2_sterol-bd_dom)
Type: Domain

This domain is involved in binding sterols, and is found in proteins such as SCP2. This domain has a 3-layer α/β/α fold, composed of α/β(3)/(crossover)/β/(α)/β.
SAP domain (SAP_dom)
Type: Domain

The SAP motif is a 35-residue motif, which has been named after SAF-A/B, Acinus and PIAS, three proteins known to contain it. The SAP motif is found in a variety of nuclear proteins involved in transcription, DNA repair, RNA processing or apoptotic chromatin degradation. As the sap motif of SAF-A has been shown to be essential for specific DNA binding activity, it has been proposed that it could be a DNA-binding motif .

A multiple alignment of the SAP motif reveals a bipartite distribution of strongly conserved hydrophobic, polar and bulky amino acids separated by a region that contains a glycine. Secondary structure predictions suggest that the SAP motif could form two α helices separated by a turn .

Some proteins known to contain a SAP motif are listed below:

Vertebrate scaffold attachment factors A and B (SAF-A/B). These two proteins are heterogeneous nuclear ribonucleoproteins (hnRNPs) that bind to AT-rich chromosomal region. It has been proposed that they couple RNA metabolism to nuclear organisation . The SAF-A protein is cleaved by caspase-3 during apoptosis .

Mammalian Acinus, a protein which induces apoptotic chromatin condensation after cleavage by caspase-3 . Acinus also contains a RNA-recognition motif.

Eukaryotic proteins of the PIAS (protein inhibitor of activated STAT) family. These proteins interact with phosphorylated STAT dimers and inhibit STAT mediated gene activation. Deletion of the first 50 amino acid residues containing the SAP domain allows the interaction of PIAS1 with STAT1 monomer .

Plant poly(ADP-ribose) polymerase (PARP). PARP is a nuclear protein that catalyzes the poly(ADP-ribosyl)ation of proteins. It is involved in responses to mild and severe oxidative stresses, by mediating DNA repair and programmed cell death processes, respectively . PARP is tightly bound to chromatin or nuclear matrix.

Arabidopsis thaliana Arp, an apurinic endonuclease-redox protein.

Yeast THO1 protein. It could be involved in the regulation of transcriptional elongation by RNA polymerase II .

Animal Ku70. Together with Ku86, it forms a DNA ends binding complex that is involved in repairing DNA double-strand breaks.

Yeast RAD18, a protein involved in DNA repair.

Neurospora crassa UVS-2, the homologue of RAD18.
RWP-RK domain (RWP-RK_dom)
Type: Domain

This domain is found in algal minus dominance proteins as well as plant proteins involved in nitrogen-controlled development . Proteins containing this domain include NIN-like proteins (NLPs) and RWP-RK domain proteins (RKDs). RWP-RK domain may serve in dimerisation and DNA binding .
Core shell protein Gag P30 (Gag_P30)
Type: Domain

Gag polyprotein plays a role in budding and is processed by the viral protease during virion maturation outside the cell . It can be cleaved into 4 chains: matrix protein p15, RNA-binding phosphoprotein p12, capsid protein p30 and nucleocapsid protein p10. This entry represents the capsid protein p30.
DAD/Ost2 (DAD/Ost2)
Type: Family

Members of this family are thought to be integral membrane proteins. Some members of this family have been shown to cause apoptosis if mutated , these proteins are known as DAD for defender against death. The family also includes the epsilon subunit of the oligosaccharyltransferase that is involved in N-linked glycosylation (also known as Ost2) .