SII-SWORD/CoKE huggingface dataset:
Gigaxonin, BTB/POZ domain (KLHL16_BTB_POZ)
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 .

Gigaxonin (also known as KLHL16) regulates microtubule-associated protein 1B (MAP1B), which is involved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability . Gigaxonin belongs to the KLHL family. Mutations in the gigaxonin gene cause giant axonal neuropathy (GAN), which is a devastating sensory and motor neuropathy . Gigaxonin binds to the ubiquitin-activating enzyme E1 through its N-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of MAP1B. It may serve as an ubiquitin substrate adaptor protein that controls MAP1B-LC degradation . This entry represents the BTB domain.
Kelch-like protein 24, BACK domain (KLHL24_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 24 (KLHL24, also known as kainate receptor-interacting protein for GluR6 (KRIP6) or protein DRE1) belongs to the KLHL family . is necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity. KLHL24 is a component of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that mediates ubiquitination of KRT14 and controls its levels during keratinocyte differentiation [

,

,

,

,

. KLHL24 binds to and regulates the GluR6a kainate receptor . It also modulates the interaction of PICK1 with GluR6 kainate receptors . Kainate receptors (KAR) are ionotropic receptors that respond to the neurotransmitter glutamate and have been implicated in epilepsy, stroke, Alzheimer's and neuropathic pain .

This entry represents the BACK domain.
Paxillin, Lim domain 2 (Paxillin_Lim_dom2)
Type: Domain

Paxillin is a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion) . Extensive tyrosine phosphorylation occurs during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens that operate through the 7TM family of G-protein-coupled receptors . Paxillin binds in vitro to the focal adhesion protein vinculin, as well as to the SH3 domain of c-Src, and, when tyrosine phosphorylated, to the SH2 domain of v-Crk . An N-terminal region has been identified that supports the binding of both vinculin and the focal adhesion tyrosine kinase, pp125Fak .

Paxillin is a 68kDa protein containing multiple domains, including four tandem C-terminal LIM domains (each of which binds 2 zinc ions); an N-terminal proline-rich domain, which contains a consensus SH3 binding site; and three potential Crk-SH2 binding sites . The predicted structure of paxillin suggests that it is a unique cytoskeletal protein capable of interaction with a variety of intracellular signalling and structural molecules important in growth control and the regulation of cytoskeletal organisation .

This entry represents the second Lim domain of Paxillin, which function as an adaptor or scaffold to support the assembly of multimeric protein. This domain shows two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms .
Kelch repeat and BTB domain-containing protein 2, BACK domain (KBTBD2_BACK)
Type: Domain

KBTBD2, also called BTB and kelch domain-containing protein 1 (BKLHD1), plays an essential role in the regulation of insulin-signaling pathway. It is a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase, which targets p85alpha, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85alpha ubiquitination and proteasome-mediated degradation. This entry represents the BACK domain .

The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs .
Paxillin/TGFB1I1, LIM domain 1 (Paxillin_TGFB1I1_LIM_dom1)
Type: Domain

Paxillin is a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion) . Extensive tyrosine phosphorylation occurs during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens that operate through the 7TM family of G-protein-coupled receptors . Paxillin binds in vitro to the focal adhesion protein vinculin, as well as to the SH3 domain of c-Src, and, when tyrosine phosphorylated, to the SH2 domain of v-Crk . An N-terminal region has been identified that supports the binding of both vinculin and the focal adhesion tyrosine kinase, pp125Fak .

Paxillin is a 68kDa protein containing multiple domains, including four tandem C-terminal LIM domains (each of which binds 2 zinc ions); an N-terminal proline-rich domain, which contains a consensus SH3 binding site; and three potential Crk-SH2 binding sites . The predicted structure of paxillin suggests that it is a unique cytoskeletal protein capable of interaction with a variety of intracellular signalling and structural molecules important in growth control and the regulation of cytoskeletal organisation .

This entry includes the transforming growth factor beta-1-induced transcript 1 (TGFB1I1, also known as Hic-5).

Hic-5 functions as a molecular adapter coordinating multiple protein-protein interactions at the focal adhesion complex and in the nucleus . Leupaxin is a transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF) .

This entry represents the first Lim domain of Paxillin and similar animal proteins, which function as an adaptor or scaffold to support the assembly of multimeric protein complexes. This domain shows two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms .
Regulator of G protein signaling 9, RGS domain (RGS9_RGS)
Type: Domain

This entry represents the RGS (Regulator of G-protein Signaling) domain of Regulator of G-protein signaling 9 (RGS9) , a member of the R7 subfamily of the RGS protein family (Neuronal RGS). RGS is a diverse group of multifunctional proteins that regulate cellular signalling events downstream of G-protein coupled receptors (GPCRs). As a major G-protein regulator, RGS domain containing 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 .

RGS9 forms constitutive complexes with G-beta-5 subunit and controls such fundamental functions as vision and behaviour . RGS9 exists in two splice isoforms: RGS9-1 which regulates phototransduction in rods and cones and RGS9-2 which regulates dopamine and opioid signalling in the basal ganglia. In addition, RGS9 was found to bind many other proteins outside of G protein signalling pathways including: mu-opioid receptor, beta-arrestin, alpha-actinin-2, NMDAR, polycystin, spinophilin, and guanylyl cyclase, among others.
Inositol polyphosphate 5-phosphatase OCRL, RhoGAP (RhoGAP_OCRL1)
Type: Domain

OCRL1 (oculocerebrorenal syndrome of Lowe 1)-like proteins contain a PH-domain at the N-terminal, a central inositol polyphosphate 5-phosphatase domain and a C-terminal Rho GAP domain. OCRL-like proteins are type II inositol polyphosphate 5-phosphatases that can hydrolyse lipid PI(4,5)P2 and PI(3,4,5)P3 and soluble Ins(1,4,5)P3 and Ins(1,3,4,5)P4, but their individual specificities vary. OCRL regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes and is involved in primary cilia assembly . This protein is associated with the oculocerebrorenal syndrome of Lowe and Dent disease 2 .

This entry represents the RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in OCRL1-like proteins. This GAP domain lacks the catalytic residue and therefore maybe inactive. The functionality of the RhoGAP domain is still unclear .
Gamma-aminobutyric acid receptor subunit alpha-1, extracellular domain (GABRA1_ECD)
Type: Domain

This entry represents the extracellular domain (ECD) of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1), a protein that is encoded by the GABRA1 gene in humans. The alpha-1 subunits form heteropentamers with other GABAAR subunits, most broadly expressed as combination of two alpha1, beta1, gamma. Mutations in this gene cause familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy type 4, and idiopathic familial generalized epilepsy . Polymorphisms in GABRA1 are also significantly associated with schizophrenia . GABRA1 has also been associated with methamphetamine abuse. The GABRA1 receptor is the specific target of the z-drug class of nonbenzodiazepine hypnotic agents and is responsible for their hypnotic and hallucinogenic effects .
ATP-binding cassette sub-family C member 9, ATP-binding cassette domain 1 (ABCC9_ATP-bd_dom1)
Type: Domain

ATP-binding cassette sub-family C member 9 (ABCC9, also known as Sulfonylurea receptor 2 or SUR2) is an ATP transporter of the ABCC/MRP family with tandem ATPase binding domains. Unlike other ABC proteins, it has no intrinsic transport function, neither active nor passive, but associates with the potassium channel proteins Kir6.1 or Kir6.2 to form the ATP-sensitive potassium (K(ATP)) channel. Within the channel complex, ABCC9 serves as a regulatory subunit that fine-tunes the gating of Kir6.x in response to alterations in cellular metabolism. It constitutes a major pharmaceutical target as it binds numerous drugs, K(ATP) channel openers and blockers, capable of up- or down-regulating channel activity .
Cystic fibrosis transmembrane conductance regulator, ATP-binding cassette domain 1 (CFTR1_ATP-bd_dom1)
Type: Domain

Cystic fibrosis transmembrane conductance regulator (CFTR, also known as ATP-binding cassette sub-family C member 7 or ABCC7) is an epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis mediating the transport of chloride ions across the cell membrane . It has adapted the ABC transporter structural motif to form a tightly regulated anion channel at the apical surface of many epithelia. It is the product of the gene mutated in patients with cystic fibrosis . CFTR displays the typical organization with two ATP-binding cassette domains and a characteristic hydrophilic domain (

) in-between.

This entry represents the first ATP-binding cassette domain of CFTR.
ATP-binding cassette sub-family C member 4, six-transmembrane helical domain 2 (ABCC4_TMD2)
Type: Domain

The ABC transporter family is a group of membrane proteins that use the hydrolysis of ATP to power the translocation of a wide variety of substrates across cellular membranes. ABC transporters minimally consist of two conserved regions: a highly conserved nucleotide-binding domain (NBD) and a less conserved transmembrane domain (TMD). Eukaryotic ABC proteins are usually organised either as full transporters (containing two NBDs and two TMDs), or as half transporters (containing one NBD and one TMD), that have to form homo- or heterodimers in order to constitute a functional protein .

This group of proteins includes ATP-binding cassette sub-family C member 4 (ABCC4, also known as Multidrug resistance-associated protein 4, MRP4) from animals. It belongs to the MRP (multidrug resistance protein) subfamily of the ATP-binding cassette (ABC) transporter family . MRP4 is a broad specificity organic anion exporter that seems to be able to mediate the transport of conjugated steroids, prostaglandins, and glutathione . It can localise to both basolateral and apical membranes in polarised cells, depending on the tissue where it is found . Together with CFTR, MRP4 functions in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes .

This entry represents the six-transmembrane helical domain 2 (TMD2) of ABCC4.
Glucosamine-fructose-6-phosphate aminotransferase, isomerising, N-terminal domain (GFAT_N)
Type: Domain

This entry represents the domain found at the N-terminal end of GFAT, the glutaminase domain, which shows a four-layer structure with two antiparallel β-sheets sandwiched between layers of α-helices .

Glucosamine:fructose-6-phosphate aminotransferase (GFAT or GlmS,

) catalyses the formation of glucosamine 6-phosphate and is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway. The final product of the hexosamine pathway, UDP-N-acetyl glucosamine, is an active precursor of numerous macromolecules containing amino sugars .

This family of sequences belong to the MEROPS peptidase family C44 (clan PB(C)), and are classified as non-peptidase homologues.
Semaphorin 4F, Sema domain (Sem4F_Sema_dom)
Type: Domain

Semaphorin-4F (Sem4F), which belongs to the class 4 transmembrane semaphorin family of proteins, plays a role in heterotypic cell-cell contacts, controls cell proliferation and suppresses tumorigenesis . In neurofibromatosis type 1 (NF1) patients, reduced Sem4F level disrupts Schwann cell/axonal interactions . Experiments using a yeast two-hybrid system show that the extreme C-terminal of Sema4F interacts with the PDZ domains of postsynaptic density protein SAP90/PSD-95, indicating possible functional involvement of Sem4F at glutamatergic synapses . A role for Sem4F in the injury response of intramedullary axotomized motoneuron has also been suggested .

This entry represents the Sema domain found at the N-terminal of Sem4F and similar proteins from mammals. It contains four disulfide bonds formed by eight conserved cysteine residues. It serves as a receptor-recognition and -binding module.
Splicing factor 1, helix-hairpin domain superfamily (SF1-HH_sf)
Type: Homologous_superfamily

This helix-hairpin domain can be found in the N-terminal region of mammalian splicing factor 1 (SF1), plant splicing factor-like protein 1 and fungal branchpoint binding proteins (BBP) . These proteins are required for pre-spliceosome formation, which is the first step of pre-mRNA splicing .

SF1 forms a complex with U2AF65 through the interaction between this domain and the C-terminal U2AF homology motif domain (UHM) of U2AF65. This domain forms a secondary, hydrophobic interface with U2AF65 (UHM) to lock the orientation of the two subunits, which is essential for cooperative formation of the ternary SF1-U2AF65-RNA complex . This domain contains a highly conserved SPSP motif at its C terminus; the phosphorylation of the SPSP motif induces a disorder-to-order transition within a novel SF1/U2AF65 interface .
Ku70, core domain (KU70_core_dom)
Type: Domain

This entry represents the central DNA-binding core domain of Ku70, which folds as a β-barrel .

Ku70 (also known as XRCC6 in animals), a single-stranded DNA-dependent ATP-dependent helicase, is a subunit of the Ku protein, which plays a key role in multiple nuclear processes such as DNA repair, chromosome maintenance, transcription regulation, DNA non-homologous end joining (NHEJ) and V(D)J recombination .

Some findings have implicated yeast Ku in telomeric structure maintenance in addition to non-homologous end-joining. Some of the phenotypes of Ku-knockout mice may indicate a similar role for Ku at mammalian telomeres . Ku70 also plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway .

Both subunits of the eukaryotic Ku heterodimer (Ku70 and Ku80) share a topology comprised of three domains: an α/β N-terminal, a central β-barrel domain and a helical C-terminal arm . Structural analysis of the Ku70/80 heterodimer bound to DNA indicates that subunit contacts lead to the formation of a highly charged channel through which the DNA passes without making any contacts with the DNA bases .
Origin recognition complex subunit 5, C-terminal (ORC5_C)
Type: Domain

This entry represents the C-terminal region of ORC5 .

The Origin Recognition Complex (ORC) is a six-subunit ATP-dependent DNA-binding complex encoded by ORC1-6 . ORC is a central component for eukaryotic DNA replication, and binds chromatin at replication origins throughout the cell cycle . ORC directs DNA replication throughout the genome and is required for its initiation . ORC bound at replication origins serves as the foundation for assembly of the pre-replicative complex (pre-RC), which includes Cdc6, Tah11 (aka Cdt1), and the Mcm2-7 complex . Pre-RC assembly during G1 is required for replication licensing of chromosomes prior to DNA synthesis during S phase . Cell cycle-regulated phosphorylation of ORC2, ORC6, Cdc6, and MCM by the cyclin-dependent protein kinase Cdc28 regulates initiation of DNA replication, including blocking reinitiation in G2/M phase .

In yeast, ORC also plays a role in the establishment of silencing at the mating-type loci Hidden MAT Left (HML) and Hidden MAT Right (HMR) . ORC participates in the assembly of transcriptionally silent chromatin at HML and HMR by recruiting the Sir1 silencing protein to the HML and HMR silencers .
Aspartate-tRNA ligase, type 1, anticodon recognition domain (Asp-tRNA-ligase_1_N)
Type: Domain

This entry represents the N-terminal, anticodon recognition domain found in a group of aspartate-tRNA ligases from mostly bacteria, eukaryotic mitochondria and some archaeal species. This domain adopts a β-barrel domain (OB fold) and is involved in binding the tRNA anticodon stem-loop .

Aspartate tRNA ligase (also known as Aspartyl-tRNA synthetase, AspRS)

is an alpha2 dimer that belongs to class IIb. Structural analysis combined with mutagenesis and enzymology data on the yeast enzyme point to a tRNA binding process that starts by a recognition event between the tRNA anticodon loop and the ligase anticodon binding module . In some species, this enzyme aminoacylates tRNA for both Asp and Asn; Asp-tRNA(asn) is subsequently transamidated to Asn-tRNA(asn).
Aspartate-tRNA ligase, type 1, core domain (AspRS_core)
Type: Domain

This entry represents the catalytic core domain found in a group of aspartate-tRNA ligases from mostly bacteria, eukaryotes and some archaeal species. This domain is primarily responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate.

Aspartate tRNA ligase (also known as Aspartyl-tRNA synthetase, AspRS)

is an alpha2 dimer that belongs to class IIb. Structural analysis combined with mutagenesis and enzymology data on the yeast enzyme point to a tRNA binding process that starts by a recognition event between the tRNA anticodon loop and the ligase anticodon binding module . In some species, this enzyme aminoacylates tRNA for both Asp and Asn; Asp-tRNA(asn) is subsequently transamidated to Asn-tRNA(asn).
Ethylene insensitive 3-like, DNA-binding domain (EIN3-like_DNA-bd)
Type: Domain

This entry represents the DNA-binding domain of EIN3 and EIN3-like proteins.

Ethylene insensitive 3 (EIN3) proteins are a family of plant DNA-binding proteins that regulate transcription in response to the gaseous plant hormone ethylene, and are essential for ethylene-mediated responses . In the presence of ethylene, dark-grown dicotyledonous seedlings undergo dramatic morphological changes collectively known as the 'triple response'. In Arabidopsis, these changes consist of a radial swelling of the hypocotyl, an exaggeration in the curvature of the apical hook, and the inhibition of cell elongation in the hypocotyl and root .
Subtelomeric hrmA-associated cluster protein AFUB_079030/YDR124W-like, helical bundle domain (AFUB_07903/YDR124W-like_hel)
Type: Domain

This entry represents a domain found in mitochondrial proteins such as Subtelomeric hrmA-associated cluster protein AFUB_079030 from Aspergillus fumigatus and YDR124W from yeast. AFUB_079030 is part of the subtelomeric hrmA-associated cluster (HAC) containing genes that alter the hyphal surface (such as reduced total chitin or increased beta-glucan exposure) and perturb inter-hyphal interactions within the developing biofilms, resulting in a loss of vertically aligned polarised growing filaments . According to structure predictions, it may adopt an helical bundle fold. Null mutant showed severe fragmentation of mitochondria and its expression is strongly induced by alpha factor. Members of this entry may have role in maintenance of mitochondrial morphology .
Twist-related protein 1, basic helix-loop-helix domain (TWIST1_bHLH)
Type: Domain

This entry represents the basic helix-loop-helix (bHLH) domain found in Twist1 and related proteins mainly from vertebrates.

Twist-related protein 1 (Twist1) is a bHLH transcriptional regulator that inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. It also represses expression of proinflammatory cytokines such as TNFA and IL1B and plays an essential role in tooth morphogenesis . In addition, Twist1 is involved in cancer development and progression . Mutations in this protein are associated with other genetic human diseases with symptoms related to malformations .