SII-SWORD/CoKE huggingface dataset:
Lmx1a, first LIM domain (Lmx1a_LIM1)
Type: Domain

This entry represents the first LIM domain of Lmx1a.

Lmx1a belongs to the LHX protein family, which features two tandem N-terminal LIM domains and a C-terminal DNA binding homeodomain. Members of LHX family are found in the nucleus and act as transcription factors or cofactors . LHX proteins are critical for the development of specialised cells in multiple tissue types, including the nervous system, skeletal muscle, the heart, the kidneys, and endocrine organs, such as the pituitary gland and the pancreas . Mouse Lmx1a is expressed in multiple tissues, including the roof plate of the neural tube, the developing brain, the otic vesicles, the notochord, and the pancreas . Human Lmx1a can be found in pancreas, skeletal muscle, adipose tissue, developing brain, mammary glands, and pituitary. The functions of Lmx1a in the developing nervous system were revealed by studies of mutant mouse. In mouse, mutations in Lmx1a result in failure of the roof plate to develop. Lmx1a may act upstream of other roof plate markers such as MafB, Gdf7, Bmp 6, and Bmp7. Further characterisation of these mice reveals numerous defects including disorganised cerebellum, hippocampus, and cortex; altered pigmentation; female sterility; skeletal defects; and behavioural abnormalities . Within pancreatic cells, the Lmx1a protein interacts synergistically with the bHLH transcription factor E47 to activate the insulin gene enhancer/promoter .

As in other LIM domains, this domain family is 50-60 amino acids in size and shares two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms. LIM domains function as adaptors or scaffolds to support the assembly of multimeric protein .
ETS-related transcription factor Elf-3, pointed domain (Elf-3_PNT)
Type: Domain

This entry represents the Pointed domain found in transcriptional regulators Elf-3 (also known as ESE-1). The Pointed domain is a putative protein-protein interaction domain.

ETS-related transcription factor Elf-3 (ESE-1) is an epithelium-specific Ets transcription factor . Ets factors are defined by a highly conserved DNA-binding domain called the Ets domain which binds to a purine-rich GGAA/T core motif in enhancer and promoter regions of target genes . Elf-3/ESE-1 has a role in inflammation , epithelial differentiation and cancer development . It has particularly high expression in the gastrointestinal tract, and may promote ulcerative colitis progression via accelerating NF-kappaB activation .
Proline-serine-threonine phosphatase-interacting protein 2, F-BAR domain (PSTPIP2_F-BAR)
Type: Domain

F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization . Proline-Serine-Threonine Phosphatase-Interacting Protein 2 (PSTPIP2) is mostly expressed in hematopoietic cells but is also expressed in the brain. It is involved in regulating cell adhesion and motility . Mutations in the gene encoding murine PSTPIP2 can cause autoinflammatory disorders such as chronic multifocal osteomyelitis and macrophage autoinflammatory disease . PSTPIP2 contains an N-terminal F-BAR domain and lacks the PEST motifs and SH3 domain that are found in PSTPIP1. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules .
ACAP3, BAR domain (ACAP3_BAR)
Type: Domain

This entry represents the BAR domain found in ACAP3. BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions .

ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3) is predicted to be an Arf GTPase activating protein (GAP) based on its similarity to the Arf6-specific GAPs ACAP1 and ACAP2 . The specific function of ACAP3 is still unknown. ACAP3 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats.
Calcium/calmodulin-dependent protein kinase type 1B, catalytic domain (CaMKI_beta_STKc)
Type: Domain

Serine/Threonine kinases (STKs) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation . The CaMK family includes CaMKI, CaMKII, CaMKIV, and CaMK kinase (CaMKK) . In vertebrates, there are four CaMKI proteins encoded by different genes (alpha, beta, gamma, and delta), each producing at least one variant. CaMKs contain an N-terminal catalytic domain and a C-terminal regulatory domain that harbors a CaM binding site. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons . The CaMKI-beta subfamily is part of a larger superfamily that includes the catalytic domains of other protein kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.
Nuclear receptor-binding protein 2, pseudokinase domain (NRBP2_PK)
Type: Domain

This entry represents the pseudokinase domain found in nuclear receptor binding protein 2 (NRBP2). This domain shows similarity to protein kinases but lacks crucial residues for catalytic activity and/or ATP binding. NRBP2 may be involved in neural progenitor cell survival .
Interleukin-1 receptor-associated kinase 3, pseudokinase domain (IRAK3_PK)
Type: Domain

This pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. IRAKs (IL-1R-associated kinases) are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation . IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signalling .

IRAK3 (or IRAK-M) is the only IRAK that does not show kinase activity. It is found only in monocytes and macrophages in humans, and functions as a negative regulator of TLR signalling including TLR-2 induced p38 activation
. It also negatively regulates the alternative NFkB pathway in a TLR-2 specific manner . IRAK3 is downregulated in the monocytes of obese people, and is associated with high SOD2, a marker of mitochondrial oxidative stress. It is an important inhibitor of inflammation in association with obesity and metabolic syndrome . The IRAK3 subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.
E3 ubiquitin-protein ligase TRIM58, RING finger, HC subclass (TRIM58_RING-HC)
Type: Domain

TRIM58, also known as protein BIA2, is an erythroid E3 ubiquitin-protein ligase induced during late erythropoiesis. It binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. It may participate in the erythroblast enucleation process through regulation of nuclear polarization. TRIM58 belongs to the C-IV 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 region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain .
Sodium-coupled monocarboxylate transporter 2, solute-binding domain (SMCT2_SLC5sbd)
Type: Domain

This entry represents the solute-binding domain found in Sodium-coupled monocarboxylate transporter 2 (SMCT2).

SMCT2 is a low-affinity transporter for short-chain fatty acids, lactate, pyruvate, and nicotinate. Human SMCT2 (hSMCT2) is encoded by the SLC5A12 gene . SMCT2 is expressed in the kidney, small intestine, skeletal muscle, and retina. In the kidney, it is expressed in the apical membrane of the proximal convoluted tubule, along the entire length of the tubule (in contrast to the high-affinity monocarboxylate transporter SMCT1, belonging to a different family, which is limited to the S3 segment of the tubule) . SMCT2 may initiate lactate absorption in the early parts of the tubule . In the retina, SMCT1 and SMCT2 may play a differential role in monocarboxylate transport in a cell type-specific manner, SMCT2 is expressed exclusively in Muller cells . SMCT2 belongs to the solute carrier 5 (SLC5) transporter family .
B0AT3, solute-binding domain (B0AT3_SLC6sbd)
Type: Domain

B0AT3 is a member of the solute carrier 6 (SLC6) transporter family. It transports glycine. Human B0AT3 (encoded by the SLC6A18 gene) is expressed in the kidney . Mutations in the SLC6A18 gene may contribute to the autosomal recessive disorder iminoglycinuria and its related disorder hyperglycinuria . SLC6A18 or its neighbouring genes are associated with increased susceptibility to myocardial infarction .
Myosin-13, motor domain (Myh13_MYSc)
Type: Domain

This entry represents the myosin motor domain of skeletal muscle myosin heavy chain 13 (also called MyHC-eo) in mammals, chicken, and green anole . Myh13 is a myosin whose expression is restricted primarily to the extrinsic eye muscles which are specialized for function in eye movement .

Class II myosins, also called conventional myosins, are the myosin type responsible for producing muscle contraction in muscle cells. Myosin II contains two heavy chains made up of the head (N-terminal) and tail (C-terminal) domains with a coiled-coil morphology that holds the two heavy chains together. The intermediate neck domain is the region creating the angle between the head and tail. It also contains 4 light chains which bind the heavy chains in the "neck" region between the head and tail. The head domain is a molecular motor, which utilizes ATP hydrolysis to generate directed movement toward the plus end along actin filaments. Class-II myosins are regulated by phosphorylation of the myosin light chain or by binding of Ca2. A cyclical interaction between myosin and actin provides the driving force. Upon ATP binding, the myosin head dissociates from an actin filament. ATP hydrolysis causes the head to pivot and associate with a new actin subunit. The release of Pi causes the head to pivot and move the filament (power stroke). Release of ADP completes the cycle. CyMoBase classifications were used to confirm and identify the myosins in this hierarchy .
Serine/threonine-protein kinase PLK3, catalytic domain (PLK3_STKc)
Type: Domain

PLK3 (polo-like kinase 3) is a serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly . It regulates angiogenesis and responses to DNA damage . Activated PLK3 mediates Chk2 phosphorylation by ATM and the resulting checkpoint activation . PLK3 phosphorylates DNA polymerase delta and may be involved in DNA repair. It also inhibits Cdc25c, thereby regulating the onset of mitosis .

STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PLKs (polo-like kinases) play important roles in cell cycle progression and in DNA damage responses. They regulate mitotic entry, mitotic exit, and cytokinesis. In general PLKs contain an N-terminal catalytic kinase domain and a C-terminal regulatory polo box domain (PBD), which is comprised by two bipartite polo-box motifs (or polo boxes) and is involved in protein interactions. There are five mammalian PLKs (PLK1-5) from distinct genes .
Serine/threonine-protein kinase 17A, catalytic domain (DRAK1_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. DRAKs (death-associated protein kinases) 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 (also called STK17A) and DRAK2. Both DRAKs are localized to the nucleus, autophosphorylate themselves, and phosphorylate myosin light chain as a substrate . Rabbit DRAK1 has been shown to induce apoptosis in osteoclasts and overexpression of human DRAK1 induces apoptosis in cultured fibroblast cells .
Serine/threonine-protein kinase LATS1, catalytic domain (LATS1_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. LATS1 functions as a tumour suppressor and is implicated in cell cycle regulation . Inactivation of LATS1 in mice results in the development of various tumours, including sarcomas and ovarian cancer . Promoter methylation, loss of heterozygosity, and missense mutations targeting the LATS1 gene have also been found in human sarcomas and ovarian cancers. In addition, decreased expression of LATS1 is associated with an aggressive phenotype and poor prognosis [

. LATS1 induces G2 arrest and promotes cytokinesis. It may be a component of the mitotic exit network in higher eukaryotes .
HSPA4L, nucleotide-binding domain (HSPA4L_NBD)
Type: Domain

Human Heat shock protein family A member 4 like (HSPA4L) is expressed ubiquitously and predominantly in the testis. It is required for normal spermatogenesis and plays a role in osmotolerance. HSPA4L belongs to the 105/110kDa heat shock protein (HSP105/110) subfamily of the HSP70-like family .

HSP105/110s are believed to function generally as co-chaperones of HSP70 chaperones, acting as nucleotide exchange factors (NEFs), to remove ADP from their HSP70 chaperone partners during the ATP hydrolysis cycle . HSP70 chaperones assist in protein folding and assembly, and can direct incompetent "client" proteins towards degradation. Like HSP70 chaperones, HSP105/110s have an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD). For HSP70 chaperones, the nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states . ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. Hsp70 chaperone activity is also regulated by J-domain proteins .
Testis-specific serine/threonine-protein kinase 3, catalytic domain (TSSK3_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. TSSK (testis-specific serine kinase) proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. There are five mammalian TSSK proteins which show differences in their localization and timing of expression . TSSK3 has been reported to be expressed in the interstitial Leydig cells of adult testis. Its mRNA levels is low at birth, increases at puberty, and remains high throughout adulthood .
Testis-specific serine/threonine-protein kinase 6, catalytic domain (TSSK6_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. TSSK (testis-specific serine kinase) proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. There are five mammalian TSSK proteins which show differences in their localization and timing of expression . TSSK6, also called SSTK, is expressed at the head of elongated sperm. It can phosphorylate histones and associate with heat shock protens HSP90 and HSC70. Male mice deficient in TSSK6 are infertile, showing spermatogenic impairment including reduced sperm counts, impaired DNA condensation, abnormal morphology and decreased motility rates .
CD80, immunoglobulin variable domain (CD80_IgV)
Type: Domain

Glycoproteins B7-1 (CD80) and B7-2 (CD86) are expressed on antigen-presenting cells and deliver the co-stimulatory signal through CD28 and CTLA-4 (CD152) on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it . CD80 contains two Ig-like domains, an amino-terminal immunoglobulin variable (IgV)-like domain characteristic of adhesion molecules and a membrane proximal immunoglobulin constant (IgC)-like domain similar to the constant domains of antigen receptors .

Members of the Ig family are components of immunoglobulin, T-cell receptors, CD1 cell surface glycoproteins, secretory glycoproteins A/C, and Major Histocompatibility Complex (MHC) class I/II molecules. In immunoglobulins, each chain is composed of one variable domain (IgV) and one or more IgC domains. These names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain. The IgV domain is responsible for antigen binding, and the IgC domain is involved in oligomerization and molecular interactions .
E3 ubiquitin-protein ligase RNF149, RING finger, H2 subclass (RNF149_RING-H2)
Type: Domain

RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that interacts with wild-type v-Raf murine sarcoma viral oncogene homologue B1 (BRAF), a RING domain-containing E3 ubiquitin ligase involved in control of gene transcription, translation, cytoskeletal organization, cell adhesion, and epithelial development. RNF149 induces the ubiquitination of wild-type BRAF and promotes its proteasome-dependent degradation. Mutated RNF149 has been found in some human breast, ovarian, and colorectal cancers. RNF149 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence .
TIF1-beta, RING finger, HC subclass (TIF1beta_RING-HC)
Type: Domain

TIF1-beta, also known as Kruppel-associated Box (KRAB)-associated protein 1 (KAP-1), belongs to the C-VI 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 region, as well as a plant homeodomain (PHD), and a bromodomain (Bromo) positioned C-terminal to the RBCC domain. It acts as a nuclear co-repressor that plays a role in transcription and in the DNA damage response .

Upon DNA damage, the phosphorylation of KAP-1 on serine 824 by the ataxia telangiectasia-mutated (ATM) kinase enhances cell survival and facilitates chromatin relaxation and heterochromatic DNA repair . It also regulates CHD3 nucleosome remodelling during the DNA double-strand break (DSB) response . Meanwhile, KAP-1 can be dephosphorylated by protein phosphatase PP4C in the DNA damage response . Moreover, KAP-1 is a co-activator of the orphan nuclear receptor NGFI-B (or Nur77) and is involved in NGFI-B-dependent transcription . It is also a coiled-coil binding partner, substrate and activator of the c-Fes protein tyrosine kinase . The N-terminal RBCC domains of TIF1-beta are responsible for the interaction with KRAB zinc finger proteins (KRAB-ZFPs), MDM2, MM1, C/EBPbeta, and the regulation of homo- and heterodimerization . The C-terminal PHD/Bromo domains are involved in interacting with SETDB1, Mi-2alpha and other proteins to form complexes with histone deacetylase or methyltransferase activity .

This entry represents the RING-HC finger found in TIF1-beta.
Tau-tubulin kinase 1, catalytic domain (TTBK1_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. TTBK is a neuron-specific kinase that phosphorylates the microtubule-associated protein tau and promotes its aggregation. Higher vertebrates contain two TTBK proteins, TTBK1 and TTBK2, both of which have been implicated in neurodegeneration. Genetic variations in TTBK1 are linked to Alzheimer's disease (AD). Hyperphosphorylated tau is a major component of paired helical filaments that accumulate in the brain of AD patients . Studies in transgenic mice show that TTBK1 is involved in the phosphorylation-dependent pathogenic aggregation of tau
.
Rhophilin-1, BRO1 domain (Rhophilin-1_BRO1)
Type: Domain

This entry represents the Bro1-like domain of Rhophilin-1, which binds both GDP- and GTP-bound RhoA. Bro1-like domains are boomerang-shaped, and part of the domain is a tetratricopeptide repeat (TPR)-like structure . In addition to this Bro1-like domain, Rhophilin-1 contains an N-terminal Rho-binding domain and a C-terminal PDZ (PS.D.-95, Disc-large, ZO-1) domain. It is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration . The isolated Bro1-like domain of Rhophilin-1 binds human immunodeficiency virus type 1 (HIV-1) nucleocapsid . Rhophilin-1 lacks the V-shaped (V) domain found in many members of the BRO1_Alix-like superfamily.
E3 ubiquitin-protein ligase RNF114, RING finger, HC subclass (RNF114_RING-HC)
Type: Domain

RNF114 (also known as Znf313) is a p21(WAF1)-targeting ubiquitin E3 ligase that interacts with X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and may play a role in p53-mediated cell-fate decisions . It is involved in immune response to double-stranded RNA in disease pathogenesis . Moreover, RNF114 interacts with A20 and modulates its ubiquitination . It negatively regulates nuclear factor-kappaB (NF-kappaB)-dependent transcription and positively regulates T-cell activation . RNF114 may play a putative role in the regulation of immune responses, since it corresponds to a novel psoriasis susceptibility gene, ZNF313 . RNF114, together with three closely related proteins: RNF125, RNF138 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).
Myosin light chain kinase 2, catalytic domain (MLCK2_STKc)
Type: Domain

STKs (serine/threonine kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLCK2 (or MYLK2) phosphorylates myosin regulatory light chain and controls the contraction of skeletal muscles . It is a key regulator of cardiac contraction . MLCK2 contains a single kinase domain near the C terminus followed by a regulatory segment containing an autoinhibitory Ca2 /calmodulin binding site.
Serine/threonine-protein kinase MRCK beta, catalytic domain (MRCKB_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. MRCK-beta (or MRCKB) is expressed ubiquitously in many tissues. MRCK is activated via interaction with the small GTPase Cdc42. MRCK/Cdc42 signalling mediates myosin-dependent cell motility . This entry includes the dimerization domain.