SII-SWORD/CoKE huggingface dataset:
Cdc1-like, metallophosphatase domain (MPP_Cdc1)
Type: Domain

Cdc1 is an endoplasmic reticulum-localized transmembrane lipid phosphatase with a metallophosphatase domain facing the ER lumen. In budding yeast, the gene encoding CDC1 is essential while nonlethal mutations cause defects in Golgi inheritance and actin polarization. Cdc1 mutant cells accumulate an unidentified phospholipid, suggesting that Cdc1 is a lipid phosphatase. Cdc1 mutant cells also have highly elevated intracellular calcium levels suggesting a possible role for Cdc1 in calcium regulation . The 5' flanking region of Cdc1 is a regulatory region with conserved binding site motifs for AP1, AP2, Sp1, NF-1 and CREB . DNA polymerase delta consists of at least four subunits - Pol3, Cdc1, Cdc27, and Cdm1 . Cdc1 belongs to the metallophosphatase (MPP) superfamily.
Rab-like protein 2 (RabL2)
Type: Family

RabL2s are novel Rab proteins identified recently which display features that are distinct from other Rabs, and have been termed Rab-like. RabL2 contains RabL2a and RabL2b, two very similar Rab proteins that share >98% sequence identity in humans. RabL2b maps to the subtelomeric region of chromosome 22q13.3 and RabL2a maps to 2q13, a region that suggests it is also a subtelomeric gene. Both genes are believed to be expressed ubiquitously, suggesting that RabL2s are the first example of duplicated genes in human proximal subtelomeric regions that are both expressed actively. Like other Rab-like proteins, RabL2s lack a prenylation site at the C terminus . RabL2 plays an important role in trafficking of ciliary GPCRs at the ciliary base in mammalian cells . RabL2 has been shown to be involved in male fertility, sperm intra-flagellar transport, and tail assembly .

Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins .
Rab20 (Rab20)
Type: Family

Rab20 is one of several Rab proteins that appear to be restricted in expression to the apical domain of murine polarized epithelial cells. It is expressed on the apical side of polarized kidney tubule and intestinal epithelial cells, and in non-polarized cells. It also localizes to vesico-tubular structures below the apical brush border of renal proximal tubule cells and in the apical region of duodenal epithelial cells. Rab20 has also been shown to colocalize with vacuolar H+-ATPases (V-ATPases) in mouse kidney cells, suggesting a role in the regulation of V-ATPase traffic in specific portions of the nephron . It was also shown to be one of several proteins whose expression is upregulated in human myelodysplastic syndrome (MDS) patients .

Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins .
Rab27a/b (Rab27a/b)
Type: Family

This entry includes Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4 . Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy . When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers .

Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins .
ADP-ribosylation factor 6 (Arf6)
Type: Family

Arf6 (ADP ribosylation factor 6) proteins localize to the plasma membrane, where they perform a wide variety of functions. In its active, GTP-bound form, Arf6 is involved in cell spreading, Rac-induced formation of plasma membrane ruffles, cell migration, wound healing, and Fc-mediated phagocytosis. Arf6 appears to change the actin structure at the plasma membrane by activating Rac, a Rho family protein involved in membrane ruffling. Arf6 is required for and enhances Rac formation of ruffles. Arf6 can regulate dendritic branching in hippocampal neurons, and in yeast it localizes to the growing bud, where it plays a role in polarized growth and bud site selection. In leukocytes, Arf6 is required for chemokine-stimulated migration across endothelial cells. Arf6 also plays a role in down-regulation of beta2-adrenergic receptors and luteinizing hormone receptors by facilitating the release of sequestered arrestin to allow endocytosis. Arf6 is believed to function at multiple sites on the plasma membrane through interaction with a specific set of GEFs, GAPs, and effectors . Arf6 has been implicated in breast cancer and melanoma cell invasion , and in actin remodelling at the invasion site of Chlamydia infection .

It's worth noting that the Arf6 homologue in Saccharomyces cerevisiae is known as Arf3 .
ADP-ribosylation factor-like protein 6 (Arl6)
Type: Family

Arl6 (Arf-like 6) forms a subfamily of the Arf family of small GTPases. Arl6 expression is limited to the brain and kidney in adult mice, but it is expressed in the neural plate and somites during embryogenesis, suggesting a possible role for Arl6 in early development . Arl6 is also believed to have a role in cilia or flagella function. Several proteins have been identified that bind Arl6, including Arl6 interacting protein (Arl6i), and SEC61beta, a subunit of the heterotrimeric conducting channel SEC61 . Based on Arl6 binding to these effectors, Arl6 is also proposed to play a role in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation .
Ras-related protein Rap2 (Rap2)
Type: Family

This entry includes Rap2a/b/c, which is part of the Rap subfamily of the Ras family. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton . In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments . In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway . The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis . Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation . A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras .

Most Ras proteins contain a lipid modification site at the C terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins .
Ras-related protein Rsr1 (Rsr1)
Type: Family

Rsr1 is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, Rsr1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with Rsr1 in vivo . In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, Rsr1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton .

Most Ras proteins contain a lipid modification site at the C terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins .
Rho-related GTP-binding protein RhoN (RhoN)
Type: Family

The Rnd proteins, which form a distinct sub-group of the Rho family of small GTP-binding proteins, have been shown to regulate the organization of the actin cytoskeleton in several tissues . RhoN (also known as Rnd2 or Rho7) is a member of the novel Rho subfamily Rnd, together with Rnd1/Rho6 and Rnd3/RhoE/Rho8. Unlike other small G proteins, Rnd2/RhoN, Rnd3/RhoE, and Rnd1/Rho6 and do not hydrolyze GTP . This is due to changes in key amino acids involved in catalysing GTP hydrolysis .

Rnd2/RhoN is transiently expressed in radially migrating cells in the brain while they are within the subventricular zone of the hippocampus and cerebral cortex. These migrating cells typically develop into pyramidal neurons. Cells that exogenously expressed Rnd2/RhoN failed to migrate to upper layers of the brain, suggesting that Rnd2/RhoN plays a role in the radial migration and morphological changes of developing pyramidal neurons, and that Rnd2/RhoN degradation is necessary for proper cellular migration. The Rnd2/RhoN GEF Rapostlin is found primarily in the brain and together with Rnd2/RhoN induces dendrite branching . Unlike Rnd1/Rho6 and Rnd3/RhoE/Rho8, which are RhoA antagonists, Rnd2/RhoN binds the GEF Pragmin and significantly stimulates RhoA activity and Rho-A mediated cell contraction . Rnd2/RhoN is also found to be expressed in spermatocytes and early spermatids, with male-germ-cell Rac GTPase-activating protein (MgcRacGAP), where it localizes to the Golgi-derived pro-acrosomal vesicle .
Rho-related GTP-binding protein RhoE (RhoE)
Type: Family

The Rnd proteins, which form a distinct sub-group of the Rho family of small GTP-binding proteins, have been shown to regulate the organization of the actin cytoskeleton in several tissues . This entry represents RhoE (also known as Rnd3 or Rho8), which is a member of the Rnd subfamily. Unlike other small G proteins, RhoE, along with two other proteins Rnd1/Rho6 and Rnd2/RhoN, does not hydrolyze GTP . This is due to changes in key amino acids involved in catalysing GTP hydrolysis .
Plantacyanin (Plantacyanin)
Type: Family

Plantacyanins belong to the phytocyanin family of blue copper proteins, a ubiquitous family of plant cupredoxins . Plantacyanin is involved in electron transfer reactions with the Cu centre transitioning between the oxidized Cu(II) form and the reduced Cu(I) form. The exact function of plantacyanin is unknown. Plantacyanins may also be stress-related proteins and be involved in plant defense responses . Plantacyanin is shown to play a role in reproduction in Arabidopsis .
Mavicyanin (Mavicyanin)
Type: Family

Mavicyanin is a glycosylated protein isolated from Cucurbita pepo medullosa (zucchini) peelings. It belongs to the phytocyanin family of blue copper proteins, a ubiquitous family of plant cupredoxins. Mavicyanin is involved in electron transfer reactions with the Cu centre transitioning between the oxidized Cu(II) form and the reduced Cu(I) form. The copper is tetrahedrally coordinated by a cysteine, 2 histidines, and a glutamine residue, like in the case of stellacyanin. The biological roles of mavicyanin have not been elucidated yet .

Phytocyanins are classified into four groups: stellacyanin, plantacyanin, uclacyanin and early nodulin groups. The domain architecture of mavicyanin reveals that it is a member of the stellacyanin group .
Early nodulin-like protein domain (ENL_dom)
Type: Domain

This entry represents a domain found early nodulin-like proteins such as ENODL1 from Arabidopsis thaliana and Oryza sativa (AtENOLD1 and OsENOLD1, respectively). These proteins may play an important role in the transport of nutrients, solutes, amino acids or hormones . These proteins belong to the phytocyanin family of blue copper proteins, a ubiquitous family of plant cupredoxins. Phytocyanin is involved in electron transfer reactions with the Cu centre transitioning between the oxidized Cu(II) form and the reduced Cu(I) form. OsENODL1 expression occurs specifically at the late developmental stage of the seeds. Members of this subgroup appear to have lost the T1 copper binding site .
Cytosolic phospholipase A2, C2 domain (C2_cPLA2)
Type: Domain

This entry represents the C2 domain found in cytosolic phospholipase A2 (cPLA2), which hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. The cooperative binding of two Ca(2+) ions to the C2 domain of cPLA2-alpha induces docking to phosphatidylcholine (PC) membranes . This domain have a type-II C2 domain topology.

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
Guanine nucleotide-binding protein subunit gamma, fungal (Ste18_fungal)
Type: Family

Yeast guanine nucleotide-binding protein subunit gamma (Ste18) is part of the G protein heterotrimer (made up of subunits alpha, beta and gamma) in the yeast pheromone response pathway. Receptor Ste2 is activated by mating pheromone, leading to GTP binding. This binding causes the beta and gamma subunits to dissociate from subunit alpha, with the resulting beta-gamma dimer functioning as the signal-transmitting component .
Nectin-1, first immunoglobulin variable domain (Nectin-1_IgV1)
Type: Domain

This entry represents the first immunoglobulin variable (IgV) domain of nectin-1 (also known as poliovirus receptor related protein 1, PRR1, PVRL1 or CD111).

Nectin-1 belongs to the nectin family comprised of four transmembrane glycoproteins (nectins-1 through -4). Nectins are synaptic cell adhesion molecules (CAMs) which facilitate adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. In addition nectins heterophilically trans-interact with other CAMs such as nectin-like molecules (Necls), nectin-1 for example, has been shown to trans-interact with Necl-1 . Nectins also interact with various other proteins, including the actin filament (F-actin)-binding protein, afadin . Mutation in the human nectin-1 gene is associated with cleft lip/palate ectodermal dysplasia syndrome (CLPED1) . Nectin-1 is a major receptor for herpes simplex virus through interaction with the viral envelope glycoprotein D .
Nectin-1, second immunoglobulin domain (Nectin-1_Ig2)
Type: Domain

This entry represents the second immunoglobulin (Ig) domain of nectin-1 (also known as poliovirus receptor related protein 1, PRR1, PVRL1 or CD111).

Nectin-1 belongs to the nectin family comprised of four transmembrane glycoproteins (nectins-1 through -4). Nectins are synaptic cell adhesion molecules (CAMs) which facilitate adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. In addition nectins heterophilically trans-interact with other CAMs such as nectin-like molecules (Necls), nectin-1 for example, has been shown to trans-interact with Necl-1 . Nectins also interact with various other proteins, including the actin filament (F-actin)-binding protein, afadin . Mutation in the human nectin-1 gene is associated with cleft lip/palate ectodermal dysplasia syndrome (CLPED1) . Nectin-1 is a major receptor for herpes simplex virus through interaction with the viral envelope glycoprotein D .
RecBCD enzyme subunit RecD, N-terminal domain superfamily (RecD_N_sf)
Type: Homologous_superfamily

RecBCD is a multi-functional enzyme complex that processes DNA ends resulting from a double-strand break. RecBCD is a bipolar helicase that splits the duplex into its component strands and digests them until encountering a recombinational hotspot (Chi site) . The RecD subunit accounts for the 5'-3' helicase activity of RecBCD. The structure of the RecD subunit resembles SF1 helicase. RecD comprises several domains - N-terminal domain, domains 1A, 1B, 2A (or 3) and 2B (in D. radiodurans RecD2) . This superfamily entry represents the N-terminal domain of RecD subunit.
ARHGAP6/36, RhoGAP domain (ARHGAP6_RhoGAP)
Type: Domain

This entry represent the RhoGAP domain found in ARHGAP6 and ARHGAP36.

Rho GTPase activating protein 6 (ARHGAP6/RHOGAP6) shows GAP activity towards RhoA, but not towards Cdc42 and Rac1 . ARHGAP6 is often deleted in microphthalmia with linear skin defects syndrome (MLS); MLS is a severe X-linked developmental disorder . ARHGAP36 is a potent antagonist of PKA signalling .
Plexin-C1, Sema domain (Plexin-C1_Sema)
Type: Domain

This entry represents the Sema domain found in Plexin-C1, which belongs to the Plexin family.
BFD-like [2Fe-2S]-binding domain superfamily (BFD-like_2Fe2S-bd_dom_sf)
Type: Homologous_superfamily

The two Fe ions are each coordinated by two conserved cysteine residues. This domain occurs alone in small proteins such as bacterioferritin-associated ferredoxin (BFD,

). The function of BFD is not known, but it may be a general redox and/or regulatory component involved in the iron storage or mobilisation functions of bacterioferritin in bacteria . This domain is also found in nitrate reductase proteins in association with the nitrite and sulphite reductase 4Fe-4S domain (

), nitrite/sulphite reductase ferredoxin-like half domain (

). It is also found in NifU nitrogen fixation proteins, in association with NifU-like N-terminal domain (

) and C-terminal domain (

).
Lysin B, C-terminal linker domain (Lysin_B_C_ter)
Type: Homologous_superfamily

This superfamily entry represents the linker domain of the mycobacteriophage Lysin B. The linker domain is composed of four α-helices connecting the C-terminal α-helix back to the side of the central β-sheet.
Glutamine-dependent NAD+ synthetase, C-terminal (NAD+_synth_C)
Type: Homologous_superfamily

This superfamily entry represents a domain found at the C terminus of glutamine-dependent NAD+ synthetase.

NAD+ biosynthesis is absolutely dependent on the activity of a multifunctional glutamine-dependent NAD+ synthetase, which catalyzes the ATP-dependent formation of NAD+ at the synthetase domain using ammonia derived from L-glutamine in the glutaminase domain .
Rab effector Noc2, FYVE domain (Noc2_FYVE)
Type: Domain

Rab effector Noc2 (also known as RPH3AL) is a Rab3 effector that mediates the regulation of secretory vesicle exocytosis in neurons and certain endocrine cells . It also functions as a Rab27 effector and is involved in isoproterenol (IPR)-stimulated amylase release from acinar cells . Noc2 contains an N-terminal Rab3A effector domain which harbors a conserved zinc finger, but lacks tandem C2 domains. The FYVE domain of Noc2 resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif .
Calsequestrin, middle TRX-fold domain (Calsequestrin_middle_dom)
Type: Domain

Calsequestrin contains three redox inactive TRX-fold domains . This entry represents the middle TRX-fold domain.

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum of cardiac and skeletal muscle . It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface.

Two forms of calsequestrin have been identified. The cardiac form is present in cardiac and slow skeletal muscle and the fast skeletal form is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation . When calcium binds there is a structural change whereby the α-helical content of the protein increases from 3 to 11% . Both forms of calsequestrin are phosphorylated by casein kinase II, but the cardiac form is phosphorylated more rapidly and to a higher degree .
Calsequestrin, N-terminal TRX-fold domain (Calsequestrin_N)
Type: Domain

Calsequestrin contains three redox inactive TRX-fold domains . This entry represents the N-terminal TRX-fold domain.

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum of cardiac and skeletal muscle . It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface.

Two forms of calsequestrin have been identified. The cardiac form is present in cardiac and slow skeletal muscle and the fast skeletal form is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation . When calcium binds there is a structural change whereby the α-helical content of the protein increases from 3 to 11% . Both forms of calsequestrin are phosphorylated by casein kinase II, but the cardiac form is phosphorylated more rapidly and to a higher degree .