SII-SWORD/CoKE huggingface dataset:
T-complex protein 10, C-terminal domain superfamily (Tcp10_C_sf)
Type: Homologous_superfamily

This entry represents a C-terminal domain found in members of the T complex protein 10 family. This domain contains unusual G repeats . Centromere protein J (also known as Centrosomal-P4.1-associated-protein, CPAP), a member of the TCP10 family, plays an important role in cell division and centrosome function by participating in centriole duplication . It inhibits microtubule nucleation from the centrosome and depolymerises taxol-stabilised microtubules . It may also be involved in the control of centriolar-microtubule growth by acting as a regulator of tubulin release . T-complex is involved in spermatogenesis in mice .

This domain, also known as TCP and G-box, is essential for the tethering of pericentriolar material (PCM), the principle site for microtubule nucleation and anchoring. It adopts an extended single-layer antiparallel β-sheet configuration . Mutations in this region are associated with primary microcephaly .
KMT2C, PHD4 domain (KMT2C_PHD4)
Type: Domain

Histone-lysine N-methyltransferases 2C (KMT2C, also known as MLL3 or homologous to ALR protein) methylates 'Lys-4' of histone H3 (H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation). It is a component of the MLL2/3 complex, which is essential for p53 transactivation of small heterodimer partner (SHP) . KMT2C functions as a circadian factor contributing to genome-scale circadian transcription . KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis .

KMT2C contains several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a high mobility group (HMG)-1 box, a SET
domain and two FY (phenylalanine tyrosine)-rich domains.

This is the forth PHD finger of KMT2C proteins.
KMT2C, PHD2 domain (KMT2C_PHD2)
Type: Domain

Histone-lysine N-methyltransferases 2C (KMT2C, also known as MLL3 or homologous to ALR protein) methylates 'Lys-4' of histone H3 (H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation). It is a component of the MLL2/3 complex, which is essential for p53 transactivation of small heterodimer partner (SHP) . KMT2C functions as a circadian factor contributing to genome-scale circadian transcription . KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis .

KMT2C contains several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a high mobility group (HMG)-1 box, a SET
domain and two FY (phenylalanine tyrosine)-rich domains.

This entry represents the second PHD finger of KMT2C proteins.
KMT2C, PHD6 domain (KMT2C_PHD6)
Type: Domain

Histone-lysine N-methyltransferases 2C (KMT2C, also known as MLL3 or homologous to ALR protein) methylates 'Lys-4' of histone H3 (H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation). It is a component of the MLL2/3 complex, which is essential for p53 transactivation of small heterodimer partner (SHP) . KMT2C functions as a circadian factor contributing to genome-scale circadian transcription . KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis .

KMT2C contains several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a high mobility group (HMG)-1 box, a SET
domain and two FY (phenylalanine tyrosine)-rich domains.

This entry represents the sixth PHD finger of KMT2C proteins.
ASAP3, ArfGAP domain (ASAP3_ArfGap)
Type: Domain

The Arf GAPs (GTPase-activating proteins) are a family of multidomain proteins with the common function of accelerating the hydrolysis of GTP bound to Arf proteins. ASAP proteins are a subtype of Arf GAPs. ASAP3 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3, also known as ACAP4, DDEFL1 (Development and Differentiation Enhancing Factor-Like 1), or centaurin beta-6), is a focal adhesion-associated Arf GAP that functions in cell migration and invasion of cancers . It is an Arf6-specific GTPase activating protein (GAP) and is co-localized with Arf6 in ruffling membranes upon EGF stimulation . ASAP3 promotes cell proliferation , being implicated in the pathogenesis of hepatocellular carcinoma and plays a role in regulating cell migration and invasion .

ASAP3 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3) contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain and ankyrin (ANK) repeats. Unlike ASAP1 and ASAP2, ASAP3 do not have an SH3 domain at the C-terminal.

This entry represents the ArfGAP domain of ASAP3. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain . Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.
5'-3' exoribonuclease 1, D1 domain superfamily (XRN1_D1_sf)
Type: Homologous_superfamily

This domain can be found in 5' to 3' exoribonuclease 1 (XRN1) which belong to a family of conserved enzymes in eukaryotes and have important functions in transcription, RNA metabolism, and RNA interference. Xrn1 in fungi and animals is primarily cytosolic and is involved in degradation of decapped mRNAs, nonsense mediated decay, microRNA decay and is essential for proper development. The Xrn1 homologue in Drosophila, known as Pacman, is required for male fertility . This domain (D1) along with 3 other domains, make up a 510-residue segment following the conserved regions found in XRNs but they are only present in XRN1 and are absent in Rat1/XRN2. The amino acid sequences of these four domains contain an excess of basic residues, suggesting that these domains might help in binding the RNA substrate. Mutational studies carried out in D1 domain show that the mutant forms had dramatically reduced nuclease activity towards ssDNA substrate indicating that domain D1 is required for Xrn1 nuclease activity .
5'-3' exoribonuclease 1, SH3-like domain superfamily (XRN1_SH3_sf)
Type: Homologous_superfamily

This is the C-terminal SH3-like domain which can be found in the exoribonuclease Xrn1. Xrn1 is a 175kDa processive exoribonuclease that is conserved from yeast to mammals which targets cytoplasmic RNA substrates marked by a 5' monophosphate for processive 5'-to-3' degradation. The Sh3-like domain in Xrn1 lacks the canonical SH3 residues normally involved in binding proline-rich peptide motifs and instead engages in non-canonical interactions with the catalytic domain. Additionally it is essential in maintaining the structural integrity of Xrn1, since partial truncation of this domain in yeast Xrn1 yields an inactive protein. There is a long loop projecting from the SH3-like domain that contacts the PAZ/Tudor domain, occluding the functional surface that binds RNA or peptide motifs containing methylated arginines, respectively, in canonical PAZ and Tudor domain .
PHD finger protein 1, PHD finger 2 (PHF1_PHD-finger2)
Type: Domain

This entry represents the second PHD finger of PHF1.

PHD finger protein 1 (PHF1) is a polycomb group (PcG) protein that plays a role in H3K27 methylation and Hox gene silencing . The Tudor domain of human PHF1 recognises both H3K36me3 and H3tK27me3 . The interaction between PHF1 and H3K36me3 stabilises the nucleosome in a conformation in which the nucleosomal DNA is more accessible to DNA-binding regulatory proteins . PHF1 is also involved in the response to DNA double-strand breaks and acts as a positive regulator of the p53 pathway .
TOM1-like protein 1, VHS domain (TOM1L1_VHS_dom)
Type: Domain

TOM1-like protein 1 (TOM1L1) is an adapter protein involved in signaling pathways. It interacts with the SH2 and SH3 domains of various signaling proteins when it is phosphorylated. TOM1L1 promotes activation of Src family tyrosine kinase Fyn, possibly by disrupting intramolecular SH3-dependent interactions . It has been implicated in multivesicular body (MVB) formation, viral egress from the cell, and cytokinesis. Its amplification enhances the metastatic progression of ERBB2-positive breast cancers .

This entry represents the N-terminal VHS (Vps27p/Hrs/Stam) domain of TOM1L1, which is found next to the GAT domain (

). This domain has a superhelical structure similar to the structure of the ARM repeats .
Myelin P0 protein, Ig-like domain (Myelin_P0_Ig-like)
Type: Domain

This entry represents the immunoglobulin (Ig)-like domain of myelin protein zero (P0), a myelin membrane adhesion molecule. P0 accounts for over 50% of the total protein in peripheral nervous system (PNS) myelin. P0 is a single-pass transmembrane glycoprotein with a highly basic intracellular domain and an Ig domain. The extracellular domain of P0 (P0-ED) is similar to the Ig variable domain, carrying one acceptor sequence for N-linked glycosylation . P0 plays a role in membrane adhesion in the spiral wraps of the myelin sheath. It is thought that homophilic interactions of the P0 extracellular domain mediate membrane juxtaposition in the extracellular space of PNS myelin .
VAV3 protein, first SH3 domain (VAV3_SH3_1)
Type: Domain

VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1 . It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration . It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity . VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains.

This entry represents the first SH3 domain of VAV3. The SH3 domain of VAV3 is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins .
Regulator of G protein signaling 6/7/9/11 (RGS6/7/9/11)
Type: Family

This family represents a diverse group of multifunctional proteins that regulate cellular signalling events downstream of G-protein coupled receptors (GPCRs). They belong to the R7 (Neuronal RGS) subfamily, which includes RGS6, RGS7, RGS9, and RGS11, all of which, in humans, are expressed predominantly in the nervous system . They form an obligatory complex with G-beta-5, and play important roles in the regulation of crucial neuronal processes . In addition, R7 proteins were found to bind many other proteins outside of the G protein signalling pathways including: m-opioid receptor, beta-arrestin, alpha-actinin-2, NMDAR, polycystin, spinophilin, guanylyl cyclase, among others. They have an RGS domain, which is an essential part of the R7 protein subfamily. These proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis .

This entry also includes Egl-10, an orthologue of human RGS7 from C. elegans.
Regulator of G-protein signalling 6/7/9/11, DHEX domain superfamily (RGS6/7/9/11_DHEX_sf)
Type: Homologous_superfamily

This entry includes a diverse group of multifunctional proteins that regulate cellular signalling events downstream of G-protein coupled receptors (GPCRs). They belong to the R7 (Neuronal RGS) subfamily, which includes RGS6, RGS7, RGS9, and RGS11, all of which, in humans, are expressed predominantly in the nervous system . They form an obligatory complex with G-beta-5, and play important roles in the regulation of crucial neuronal processes . In addition, R7 proteins were found to bind many other proteins outside of the G protein signalling pathways including: m-opioid receptor, beta-arrestin, alpha-actinin-2, NMDAR, polycystin, spinophilin, guanylyl cyclase, among others. They have an RGS domain, which is an essential part of the R7 protein subfamily. These proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis . This entry also includes egl-10, an orthologue of human RGS7 from C. elegans.

This is the DHEX (DEP helical extension) domain superfamily. The DHEX domain is located next to N-terminal Dishevelled/Egl-10/Pleckstrin homology (DEP) domain. These constitute a site of major allosteric regulation of the complex via association with GPCRs and small SNARE-like membrane proteins. Both the DEP and DHEX domains are necessary, but not sufficient, to bind anchoring proteins such as RGS9 anchor protein. DHEX has no close structural homologues .
Peroxidasin, Ig-like domain 3 (Peroxidasin_Ig-like3)
Type: Domain

Peroxidasin is a secreted heme peroxidase which is involved in hydrogen peroxide metabolism and peroxidative reactions in the cardiovascular system . It is a multidomain peroxidase that contain a signal peptide, several (e.g., five in Drosophila or one in Homo sapiens) leucine-rich regions, followed by four immunoglobulin-like domains, a linking region, the peroxidase domain, and a carboxy terminal Willebrand type C protein-protein interaction domain .

This entry represents the third immunoglobulin (Ig)-like domain of vertebrate peroxidasin.
Glial cell line-derived neurotrophic factor, TGF-beta-like domain (GDNF_TGF-b-like)
Type: Domain

This group represents glial cell line-derived neurotrophic factor (GDNF). This is a neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake . Defects in GDNF are a cause of congenital central hypoventilation syndrome (also known as Ondine's curse) and are also linked with Hirschsprung disease .

This entry represents the transforming growth factor beta (TGF-beta)-like domain of GDNF.
RNA exonuclease REXO1/REXO3/REXO4-like (REXO1/3/4-like)
Type: Family

This entry represents a family of eukaryotic proteins that function as exonucleases, including RNA exonuclease 1 homologue from humans (REXO1), RNA exonuclease 3 from Candida albicans, RNA exonuclease 4 from Saccharomyces cerevisiae (REXO4), and Putative small RNA degrading nuclease 1-5 from Arabidopsis thaliana (SDN1-5), all of which appear to have exonuclease activity . Interferon-stimulated gene 20 kDa proteins from mammals (also known as apoptosis-enhancing nuclease AEN) also included in this family, which are exonucleases with activity against single- and double-stranded DNA and RNA and mediates p53-induced apoptosis . They act also as interferon-induced antiviral exoribonucleases .
Rabphilin/Doc2, first C2 domain (Rabphilin_Doc2_C2A)
Type: Domain

This entry includes Rabphilin and Doc2. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: Rabphilin contains an N-terminal Rab-binding domain (RBD), whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID) .

This is the first C2 domain, referred to as C2A, found in Rabphilin and Doc2 proteins. In Doc2 alpha and beta, it exhibits Ca2+-dependent phospholipid-binding activity .
Gamma-aminobutyric acid receptor subunit alpha-2, extracellular domain (Gabra-2_ECD)
Type: Domain

This entry represents the extracellular domain of Gamma-aminobutyric acid receptor subunit alpha-2 (Gabra-2). This protein has a binding site for benzodiazepines (psychoactive drugs known to reduce anxiety) and is a target for treating behavioural disorders including alcohol dependence, and drug use. It is associated with reward behaviour when it activates the insula, the part of the cerebral cortex responsible for emotions, and with GABAergic modulation of prolactin secretion , This domain, which is located towards the N-terminal of the protein, plays a direct role in interactions between the presynaptic and postsynaptic elements .
Gamma-aminobutyric acid receptor subunit alpha 1-6, transmembrane domain (Gabra-1-6_TM)
Type: Domain

This entry represents the transmembrane domain (TM) of the six alpha subunits of Gamma-aminobutyric acid receptor (Gabra-1-6). A decline in the function of this complex, which acts as an anionic channel that mediates fast inhibitory synaptic transmission, triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy . This domain consists of four transmembrane-spanning α-helical segments that are linked by loops. The intracellular loop that links the first two α-helical segments determines the ion selectivity of the channel .
Dedicator of cytokinesis protein 1/5, SH3 domain (DOCK1_5_SH3)
Type: Domain

DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane . DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) . All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker).

DOCK1, also called Dock180, and DOCK5 are class A DOCKs and are atypical guanine nucleotide exchange factors (GEFs) that lack the conventional Dbl homology (DH) domain. DOCK1 interacts with the scaffold protein Elmo and the resulting complex functions upstream of Rac in many biological events including phagocytosis of apoptotic cells, cell migration and invasion . DOCK5 functions upstream of Rac1 to regulate osteoclast function . Class A DOCKs also contain an SH3 domain at the N-terminal region and a PxxP motif at the C-terminal; they are specific GEFs for Rac.
Dedicator of cytokinesis protein 1, C2 domain (DOCK1_C2)
Type: Domain

DOCK1, also called Dock180, is a class A DOCK and an atypical guanine nucleotide exchange factor (GEF). DOCK1 interacts with the scaffold protein Elmo and the resulting complex functions upstream of Rac in many biological events including phagocytosis of apoptotic cells, cell migration and invasion . Class A DOCKs contain a C2 domain and additionally, an SH3 domain at the N-terminal region and a PxxP motif at the C-terminal; they are specific GEFs for Rac.

This entry represents the C2 domain of DOCK1 . This domain has been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3).
Kelch-like protein 14, BACK domain (KLHL14_BACK)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like protein 14 (KLHL14) belongs to the KLHL family . Its is also known as Printor (protein interactor of torsinA). It selectively binds to the ATP-free form, but not to the ATP-bound form of torsinA, suggesting a role for Printor as a cofactor rather than a substrate of the AAA+ protein torsinA and is implicated in dystonia pathogenesis .

This entry represents the BACK domain.
Kelch-like protein 32, BACK domain (KLHL32_BACK)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like protein 32 (KLHL32), also called BTB and kelch domain-containing protein 5 (BKLHD5) , contains a BTB domain and kelch repeats, characteristics of a kelch family protein. Its function remains unclear. Deletion of KLHL32 may be associated with Tourette syndrome and obsessive-compulsive disorder . Its function is not clear.

This entry represents the BACK domain of KLHL32.
Glycine receptor subunit beta, transmembrane domain (GlyR_beta_TM)
Type: Domain

Glycine receptors (GlyR) are ligand-gated chloride channels that function as major inhibitory neurotransmitters (NT) in the adult vertebrate central nervous system (CNS). Glycinergic synapses have a well-established role in the processing of motor and sensory information that controls
movement, vision and audition . Strychnine acts as a competitive antagonist of glycine binding, thereby reducing the activity of inhibitory neurons. Whilst glycine is the principal physiological agonist at GlyRs, taurine and beta-alanine also behave as agonists .

This entry represents the transmembrane (TM) domain of the beta subunit of GlyR. It consists of four transmembrane-spanning α-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel.