SII-SWORD/CoKE huggingface dataset:
Plexin-D1, sema domain (Plexin-D1_Sema)
Type: Domain

Plexin D1 belongs to the plexin family, whose members cell surface receptors for extracellular signals of the semaphorin family . Plexin D1 is the receptor of Sema3E that regulates axon guidance, angiogenesis, tumour growth, and tumour metastasis . In endothelial cells, Sema3E-PlexinD1 inhibit cell-substrate adhesion and exert an anti-angiogenic function, while in cancer cells they have been shown to have a pro-tumorigenic role . The Sema domain is located at the N terminus and contains four disulfide bonds formed by eight conserved cysteine residues. It serves as a ligand-recognition and -binding module.
Piccolo, FYVE-related domain 1 (PCLO_FYVE1)
Type: Domain

Protein piccolo, also known as aczonin, is a neuron-specific presynaptic active zone scaffolding protein that mainly interacts with a detergent-resistant cytoskeletal-like subcellular fraction and is involved in the organization of the interplay between neurotransmitter vesicles, the cytoskeleton, and the plasma membrane at synaptic active zones . It binds profilin, an actin-binding protein implicated in actin cytoskeletal dynamics . It also functions as a presynaptic low-affinity Ca2 sensor and has been implicated in Ca2 regulation of neurotransmitter release .
Transposase A from transposon Tn554, C-terminal catalytic domain (INT_tnpA_C_Tn554)
Type: Domain

This entry represents the C-terminal domain of transposase A from transposon Tn554, which belongs to a DNA breaking-rejoining enzyme superfamily. The catalytic domain contains six conserved active site residues. The recombination reaction involves cleavage of a single strand of a DNA duplex by nucleophilic attack of a conserved tyrosine to give a 3' phosphotyrosyl protein-DNA adduct. In the second rejoining step, a terminal 5' hydroxyl attacks the covalent adduct to release the enzyme and generate duplex DNA. Many DNA breaking-rejoining enzymes also have N-terminal domains, which show little sequence or structure similarity .
RelA-associated inhibitor, SH3 domain (SH3_iASPP)
Type: Domain

RelA-associated inhibitor, also known as iASPP, is an oncoprotein that inhibits the apoptotic transactivation potential of p53 . It is upregulated in human breast cancers expressing wild-type p53 , in acute leukemias regardless of the p53 mutation status , as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance . iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family . It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53.

This entry represents the SH3 domain found in iASPP.
RNF135, PRY/SPRY domain (RNF135_SPRY_PRY_dom)
Type: Domain

This entry represents the C-terminal domain of RING finger protein RNF135. This domain contains the distinct N-terminal PRY subdomain followed by the SPRY subdomain. RNF135 ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Normally, RIG-I is activated by TRIM25 in response to viral infection, leading to activation of the RIG-I signalling pathway, thus resulting in type I interferon production to limit viral replication. However, RNF135, consisting of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs and showing sequence similarity to TRIM25, acts as an alternative factor that promotes RIG-I activation independent of TRIM25 . RNF135 interacts with RIG-I via the PRY-SPRY domain . Mutations of the RNF135 gene cause phenotypic abnormalities including overgrowth .
Sodium/myo-inositol cotransporter SMIT (SMIT)
Type: Family

Human SMIT is a high-affinity myo-inositol transporter, and is expressed in brain, heart, kidney, and lung. Inhibition of myo-inositol uptake, through down-regulation of SMIT, may be a common mechanism of action of mood stabilizers, including lithium, carbamazepine, and valproate . SMIT is encoded by the SLC5A3 gene, which is a candidate gene for pathogenesis of nervous system dysfunction in Down syndrome (DS) . The SNP, 21q22 near SLC5A3-MRPS6-KCNE2, has been associated with coronary heart disease, cardiovascular disease, and myocardial infarction . SMIT may also be involved in the pathogenesis of congenital cataract . SMIT also plays roles in osteogenesis, bone formation, and bone mineral density determination. SMIT belongs to the solute carrier 5 (SLC5) transporter family .
WWOX, classical (c)-like SDR domain (WWOX_SDR_c-like)
Type: Domain

This entry represents the classical-like SDR domain of human WWOX and related proteins. Proteins in this entry share the glycine-rich NAD-binding motif of the classical SDRs, have a partial match to the canonical active site tetrad, but lack the typical active site Ser .
WDFY1, FYVE domain (WDFY1_FYVE)
Type: Domain

WDFY1 is a novel single FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. WDFY1 to early endosomes requires an intact FYVE domain and is inhibited by wortmannin, a PI3-kinase inhibitor. In addition to FYVE domain, WDFY1 harbours multiple WD-40 repeats. This entry represent the FYVE domain of WDFY1 .
Rho-related GTP-binding protein RhoG (RhoG)
Type: Family

RhoG is a GTPase with high sequence similarity to members of the Rac subfamily, including the regions involved in effector recognition and binding. However, RhoG does not bind to known Rac1 and Cdc42 effectors, including proteins containing a Cdc42/Rac interacting binding (CRIB) motif. Instead, RhoG interacts directly with Elmo, an upstream regulator of Rac1, in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1 . The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Thus RhoG activates Rac1 through Elmo and Dock180 to control cell morphology . RhoG has also been shown to play a role in caveolar trafficking and has a novel role in signaling the neutrophil respiratory burst stimulated by G protein-coupled receptor (GPCR) agonists . Most Rho 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 Rho proteins.
FCHO1, F-BAR domain (FCHO1_F-BAR)
Type: Domain

F-BAR domain only protein 1 (FCHo1) belongs to the F-BAR family, whose members have been implicated in cell membrane processes such as membrane invagination, tubulation and endocytosis . FCHo1 functions in an early step of clathrin-mediated endocytosis. It has a membrane binding/bending activity and the ability to recruit proteins essential to the formation of functional clathrin-coated pits . It contains an N-terminal F-BAR domain and a C-terminal domain of unknown function named SAFF which is also present in FCHo2 and endophilin interacting protein 1.
CAPN2, penta-EF hand, calcium binding motif (EFh_PEF_CAPN2)
Type: Domain

This entry represents the Ca2 -binding penta-EF-hand (PEF) domain found in CAPN2 (also known as Calpain 2).

CAPN2 is a ubiquitously expressed Ca2 -dependent intracellular cysteine protease that contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2 -binding penta-EF-hand (PEF) domain . The catalytic subunit CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer . CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons . It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell .

The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation . It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signalling cascade . Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer . Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion . The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory . In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation . Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation . The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.
RING1 , RING finger, HC subclass (RING1_RING-HC)
Type: Domain

RING1 is a transcriptional repressor associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. It is a core component of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase that transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119 . PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing . RING1 interacts with multiple PcG proteins and displays tumorigenic activity
. It also shows zinc-dependent DNA binding activity. Moreover, RING1 inhibits transactivation of the DNA-binding protein recombination signal binding protein-Jkappa (RBP-J) by Notch through interaction with the LIM domains of KyoT2 . RING1 contains a C3HC4-type RING-HC finger .
Frizzled-7, cysteine-rich Wnt-binding domain (Frizzled-7_CRD)
Type: Domain

This entry represents the cysteine-rich domain (CRD) of the Frizzled 7 (Fz7) receptor that is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation . Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway . CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Xenopus Fz7 is important in Wnt/beta-catenin signaling pathways controlling the transcriptional activation of target genes Siamois and Xnr3 in the animal caps of late blastula .
Serine/threonine-protein kinase 10, catalytic domain (STK10_STKc)
Type: Domain

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. STK10/LOK, also called polo-like kinase kinase 1 in Xenopus (xPlkk1) , is highly expressed in lymphocytes and is responsible in regulating leukocyte function associated antigen (LFA-1)-mediated lymphocyte adhesion . It plays a role in regulating the CD28 responsive element in T cells , and may also function as a regulator of polo-like kinase 1 (Plk1), a protein which is overexpressed in multiple tumour types .
Plexin-A1, Sema domain (Plexin-A1_Sema)
Type: Domain

Plexin A1 is found in both the nervous and immune systems. Its external Sema domain is also shared by semaphorin proteins. In the nervous system, Plexin A1 mediates Sema3A axon guidance function by interacting with the Sema3A coreceptor neuropilin, resulting in actin depolarization and cell repulsion . In the immune system, Plexin A1 mediates Sema6D signaling by binding to the Sema6D-Trem2-DAP12 complex on immune cells and osteoclasts to promote Rac activation and DAP12 phosphorylation . In gene profiling experiments, Plexin A1 was identified as a CIITA (class II transactivator) regulated gene in primary dendritic cells (DCs) .
RNase L, RNase domain (RNase-L_RNase)
Type: Domain

Ribonuclease L (RNase L) is a highly regulated, latent endoribonuclease (thus the 'L' in RNase L) and is widely expressed in most mammalian tissues. It is involved in the mediation of the antiviral and pro-apoptotic activities of the interferon-inducible 2-5A system, which blocks infections by certain types of viruses through cleavage of viral and cellular single-stranded RNA . RNase L is unique in that it is composed of three major domains; N terminus regulatory ankyrin repeat domain (ARD), followed by a linker, a protein kinase (PK)-like domain and a C-terminal ribonuclease (RNase) domain. The RNase domain has homology with IRE1, also containing both a kinase and an endoribonuclease, that functions in the unfolded protein response (UPR) . RNase L has been shown to have an impact on the pathogenesis of prostate cancer; the RNase L gene, RNASEL, has been identified as a strong candidate for the hereditary prostate cancer 1 (HPC1) allele . The broad range of biological functions of RNase offers a possibility for RNase L as a therapeutic target.

This entry represents the RNase domain of RNase L.
EPH-A6 , SAM domain (EPH-A6_SAM)
Type: Domain

This entry represents the SAM (sterile alpha motif) domain of EPH-A6 (Ephrin type-A receptor 6), a receptor tyrosine kinase. It is a C-terminal potential protein-protein interaction domain located in the cytoplasmic region of EPH-A6 receptors and appears to mediate cell-cell initiated signal transduction . Eph-A6 gene is preferentially expressed in the nervous system. EPH-A6 receptors are involved in primate retina vascular and axon guidance, and in neural circuits responsible for learning and memory . EphA6 gene was significantly down regulated in colorectal cancer and in malignant melanomas. It is a potential molecular marker for these cancers .
IRAK3, death domain (IRAK3_death)
Type: Domain

This entry represents the death Domain (DD) of IRAK3 (also known as IRAK-M). IRAKs are essential components of innate immunity and inflammation in mammals and other vertebrates . They are involved in signal transduction pathways involving IL-1 and IL-18 receptors, Toll-like receptors(TLRs), nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs) . IRAKs contain an N-terminal DD domain and a C-terminal kinase domain. IRAK3 is an inactive kinase present only in macrophages in an inducible manner . It is a negative regulator of TLR signalling and it contributes to the attenuation of NF-kB activation .

DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signalling pathways and can recruit other proteins into signalling complexes .
TRIM54, RING finger, HC subclass (TRIM54_RING-HC)
Type: Domain

TRIM54, also known as MuRF-3, is an E3 ubiquitin-protein ligase involved in ubiquitin-mediated muscle protein turnover. It is ubiquitously detected in all fibre types, and is developmentally upregulated, associates with microtubules, the sarcomeric M-line (this report) and Z-line, and is required for microtubule stability and myogenesis. It associates with glutamylated microtubules during skeletal muscle development, and is required for skeletal myoblast differentiation and development of cellular microtubular networks. MuRF-3 controls the degradation of four-and-a-half LIM domain (FHL2) and gamma-filamin and is required for maintenance of ventricular integrity after myocardial infarction (MI) .
TRIM25, PRY/SPRY domain (TRIM25_SPRY_PRY)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM25 proteins. TRIM25 (also called Efp) ubiquitinates the N terminus of the viral RNA receptor retinoic acid-inducible gene-I (RIG-I) in response to viral infection, leading to activation of the RIG-I signalling pathway, thus resulting in type I interferon production to limit viral replication. It has been shown that the influenza A virus targets TRIM25 and disables its antiviral function .
E3 ubiquitin-protein ligase COP1 (COP1)
Type: Family

COP1 is a RING finger-type ubiquitin E3 ligase. In Arabidopsis, it is a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis) . In mammals, it functions as an E3 ubiquitin-protein ligase involved in tumorigenesis, gluconeogenesis, and lipid metabolism. It is regulated by the COP9 signalosome and is involved in 14-3-3 delta ubiquitin-mediated degradation . COP1 contains a classic leucine-rich NES and a novel bipartite NLS bridged by a RING finger domain .
Protein sel-1 homolog 3 (Sel-1L3)
Type: Family

The function of Sel-1L3 (sel-1 homolog 3) is not clear.
Endothelial cell-selective adhesion molecule (ESAM)
Type: Family

ESAM (Endothelial cell-selective adhesion molecule) is an adhesion molecule that belongs to the immunoglobulin family. It is selectively expressed by endothelial cells
.
Immunoglobulin superfamily member 11 (IGSF11)
Type: Family

Immunoglobulin superfamily member 11 (IGSF11), also known as Bt-IGSF, is a cell adhesion molecule that belongs to the immunoglobulin family. Its expression is highly restricted to brain and testis . In mice, it has been shown to regulate the development of the cerebellum and play a major role in male fertility .
Coiled-coil domain-containing protein 126 (CCDC126)
Type: Family

The function of Coiled-coil domain-containing protein 126 (CCDC126) is not clear.
CDK15, catalytic domain (CDK15_STKc)
Type: Domain

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK15 (also known as PFTAIRE-2) is also referred to as ALS2CR7 (amyotrophic lateral sclerosis 2 (juvenile) chromosome region candidate 7). It has been shown to confer TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance to cancer cells via phosphorylation of survivin . It may be associated with amyotrophic lateral sclerosis 2 (ALS2), an autosomal recessive form of juvenile ALS. It shares sequence similarity with Cyclin-Dependent Kinases (CDKs), which belong to a large family of STKs that are regulated by their cognate cyclins. In general, CDKs and cyclins are involved in the control of cell-cycle progression, transcription, and neuronal function .
PKHF1, FYVE domain (PKHF1_FYVE)
Type: Domain

This entry represents the FYVE zinc finger domain of Pleckstrin homology domain-containing family F member 1 (PKHF1), also known as Phafin-1. The function of PKHF1 is unknown.
Serine/threonine-protein kinase 17B, catalytic domain (ST17B_STKc)
Type: Domain

This entry represents the catalytic domain of ST17B (Serine/threonine-protein kinase 17B), also known as DRAK2 .

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. DRAKs were named based on their similarity (around 50% identity) to the kinase domain of DAPKs. They contain an N-terminal kinase domain and a C-terminal regulatory domain. Vertebrates contain two subfamily members, DRAK1 and DRAK2. Both DRAKs are localized to the nucleus, autophosphorylate themselves, and phosphorylate myosin light chain as a substrate. DRAK2 has been implicated in inducing or enhancing apoptosis in beta cells, fibroblasts, and lymphoid cells, where it is highly expressed . It is involved in regulating many immune processes including the germinal centre (GC) reaction, responses to thymus-dependent antigens, activated T cell survival, memory T cell responses . It may be involved in the development of autoimmunity .
TRIM42, RING-HC finger (TRIM42_RING-HC)
Type: Domain

Tripartite motif-containing protein 42 (TRIM42) belongs to the C-III subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil domain. It also has a novel cysteine-rich motif N-terminal to the RBCC domain, as well as a COS (carboxyl-terminal subgroup one signature) box and a fibronectin type-III (FN3) domain positioned C-terminal to the RBCC domain. TRIM42 can interact with TRIM27, a known cancer-associated protein. Its precise biological function remains unclear .
RSK3, C-terminal catalytic domain (RSK3_STKc)
Type: Domain

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RSK3 (also known as RPS6KA2) is one of four RSK isoforms (RSK1-4) from distinct genes present in vertebrates. RSK3 binds muscle A-kinase anchoring protein (mAKAP)-b directly and regulates concentric cardiac myocyte growth . The RSK3 gene, RPS6KA2, is a putative tumour suppressor gene in sporadic epithelial ovarian cancer and variations to the gene may be associated with rectal cancer risk .

RSKs (90kDa ribosomal S6 kinases) contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. They are activated by signalling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival .
Serine/threonine-protein kinase Nek9, catalytic domain (Nek9_STKc)
Type: Domain

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Nek9, also called Nercc1, is primarily a cytoplasmic protein but can also localize in the nucleus. It is involved in modulating chromosome alignment and splitting during mitosis. It interacts with the gamma-tubulin ring complex and the Ran GTPase, and is implicated in microtubule organization . Nek9 associates with FACT (FAcilitates Chromatin Transcription) and modulates interphase progression . It also interacts with Nek6, and Nek7, during mitosis, resulting in their activation. Nek9 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control .
Homeobox protein MNX1/Ceh-12 (MNX1/Ceh-12)
Type: Family

This entry represents a group of homeobox proteins, including Motor neuron and pancreas homeobox protein 1 (MNX1) from mammals and Ceh-12 from C. elegans. Mutations in the MNX1 gene cause Currarino syndrome (CURRAS), a triad composed of partial sacral agenesis with intact first sacral vertebra ("sickle-shaped sacrum"), presacral mass, and anorectal malformations .
SPATA6 family (SPATA6_fam)
Type: Family

This entry includes Spermatogenesis-associated protein 6 (SPATA6) and SPATA6-like proteins. SPATA6 has similarity with the motor domain of kinesin related proteins and the Caenorhabditis elegans neural calcium sensor protein (NCS-2) . It plays a role in linking the developing flagellum to the head during late spermiogenesis by being involved in the formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece . The function of SPATA6L is not clear.
RWD domain-containing protein 4 (RWDD4)
Type: Family

The function of RWD domain-containing protein 4 (RWDD4) is not clear.