SII-SWORD/CoKE huggingface dataset:
Transcription factor E3, bHLHzip domain (bHLHzip_TFE3)
Type: Domain

The MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF (microphthalmia-associated transcription factor) and related family members TFE3, TFEB and TFEC . The transcription factors heterodimerize with each other and recognise the same DNA sequences . They recognise and bind E-box sequences (3'-CANNTG-5').

This entry represents the basic Helix-Loop-Helix-zipper domain of transcription factor E3 (TFE3). In association with TFEB, TFE3 activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4+ T-cells and thymus-dependent humoral immunity. It also has also a role in osteoclast development . TFE3 specifically recognises the MUE3 box, a subset of E-boxes, present in the immunoglobulin enhancer . For efficient DNA-binding, TFE3 requires dimerisation with itself or with another MiT/TFE family member, such as TFEB or MITF.
Pseudokinase tribbles family/serine-threonine-protein kinase 40 (Tribbles/Ser_Thr_kinase_40)
Type: Family

Tribbles encode an evolutionarily conserved protein family that influences proliferation, motility, metabolism, and oncogenic transformation. Originally identified in Drosophila, tribbles homologues are characterised by a central serine/threonine kinase-like domain (KD) and a C-terminal binding site for E3 ubiquitin ligases. Although the KD is the defining feature of the tribbles family, these proteins are considered to be catalytically inactive because they lack conserved residues from the characteristic adenosine triphosphate binding site and catalytic core motif within the KD .

This entry represents the tribbles family, including TRB-1, TRB-2 and TRB-3, the mammalian homologues of Drosophila tribbles. This entry also matches serine/threonine-protein kinase 40 (STK40). This kinase may be a negative regulator of NF-kappa-B and p53-mediated gene transcription .
Tribbles homologue 1, pseudokinase domain (TRB1_pseudokinase_dom)
Type: Domain

Tribbles encode an evolutionarily conserved protein family that influences proliferation, motility, metabolism, and oncogenic transformation. Originally identified in Drosophila, tribbles homologues are characterised by a central serine/threonine kinase-like domain (KD) and a C-terminal binding site for E3 ubiquitin ligases. Although the KD is the defining feature of the tribbles family, these proteins are considered to be catalytically inactive because they lack conserved residues from the characteristic adenosine triphosphate binding site and catalytic core motif within the KD .

TRB-1, TRB-2 and TRB-3 are the mammalian homologues of Drosophila tribbles. This entry represents the pseudokinase domain of TRB-1, which interacts with and regulates activation of MAP kinases. TRB-1 may not display kinase activity . It regulates vascular smooth muscle cell proliferation and chemotaxis through the JNK signalling pathway. It is found to be down-regulated in human acute myeloid leukaemia (AML) and may play a role in the pathogenesis of the disease. It has also been identified as a potential biomarker for antibody-mediated allograft failure .
Tyrosine-tRNA ligase, bacterial-type, type 1 (Tyr-tRNA-ligase_bac_1)
Type: Family

Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) (

) are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase .

Two main groups can be distinguished among tyrosine-tRNA ligases: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry represents contains bacterial and organellar eukaryotic tyrosine-tRNA ligases classified as type 1.

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases .
Tyrosine-tRNA ligase, bacterial-type, type 2 (Tyr-tRNA-ligase_bac_2)
Type: Family

Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) (

) are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase .

Two main groups can be distinguished among tyrosine-tRNA ligase: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry belongs to the first group and contains tyrosein-tRNA ligase classified as type 2.

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases .
Tryptophan-tRNA ligase, bacterial-type (Trp-tRNA-ligase_bac-type)
Type: Family

Tryptophan-tRNA ligases are widely distributed, being found in archaea, bacteria and eukaryotes. This entry represents a subgroup of the enzymes that contains bacterial and eukaryotic proteins.

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases .
Immunoglobulin J chain (Ig_J)
Type: Family

Immunoglobulin J serves to link two monomer units of either IgM or IgA. In the case of IgM, the J chain-joined dimer is a nucleating unit for the IgM pentamer, and in the case of IgA it induces larger polymers. It also help to bind these immunoglobulins to the secretory component .
PEX5/PEX5L (PEX5/PEX5L)
Type: Family

Peroxisomal proteins catalyse metabolic reactions. The import of proteins from the cytosol into the peroxisomes matrix depends on more than a dozen peroxin (PEX) proteins, among which PEX5 and PEX7 serve as receptors that shuttle proteins bearing one of two peroxisome-targeting signals (PTSs) into the organelle. PEX5 is the PTS1 receptor, while PEX7 is the PTS2 receptor. In plants, PEX7 depends on PEX5 binding to deliver PTS2 cargo into the peroxisome, and PEX7 also facilitates PEX5 accumulation and import of PTS1 cargo into peroxisomes .

This entry include PEX5 (also known as PTS1R) from animals, fungi and plants. This entry also includes PEX5L from vertebrates. PEX5 binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import . Based on subcellular localization and binding properties mammalian PEX5 may function as a regulator in an early step of the PTS1 protein import process . PEX5L acts as an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence . Interestingly, although PEX5 and PEX5L have structurally similar binding at their TPR domains, they bind to different substrates in vivo .
Islet cell autoantigen 1/Ica1-like (Islet_autoAg_Ica1/Ica1-like)
Type: Family

Islet cell autoantigen 1 (Ica1) and its Caenorhabditis elegans homologue, Ric19 (resistance to inhibitors of cholinesterase protein 19), may play a role in neurotransmitter secretion .

This entry includes Ica1 and homologues, and also proteins known as Ica1-like, which are found in mammals and whose function has not been described.
Transcription factor DEAF-1 (TF_DEAF-1)
Type: Family

Deformed epidermal autoregulatory factor-1 (DEAF-1) was first isolated in Drosophila melanogaster as a novel DNA-binding protein . Since then, several orthologues in mammals have been identified. In Drosophila, DEAF-1 plays an important role in embryonic development, particularly in the segmentation stage following cuticle secretion. In mammals it regulates different processes, including epithelial cell proliferation and side-branching in the mammary gland and it is required for neural tube closure and skeletal patterning . Mutations in DEAF-1 cause intellectual disability and behavioural problems, most likely as a result of impaired transcriptional regulation by DEAF1 .
T-cell surface glycoprotein CD3 zeta subunit (T-cell_CD3_zeta)
Type: Family

The TCR complex of T-lymphocytes consists of either a TCR alpha/beta or TCR gamma/delta heterodimer co-expressed at the cell surface with the invariant subunits of CD3 labelled gamma, delta, epsilon, zeta, and eta . The zeta subunit forms either homodimers or heterodimers with eta , but eta homodimers have not been observed. The structure of the zetazeta transmembrane dimer consists of a left-handed coiled coil with polar contacts. Two aspartic acids are critical for zetazeta dimerisation and assembly with TCR .

This family includes the zeta subunit from the CD3 T-Cell co-receptor.
Sphingomyelin phosphodiesterase 4 (Sphingomy_SMPD4)
Type: Family

Sphingomyelin phosphodiesterase 4 (also known as neutral sphingomyelinase 3) catalyses the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide .
DAP1/DAPL1 (DAP1/DAPL1)
Type: Family

This family includes death-associated protein 1 (DAP1) and death-associated protein-like 1 (DAPL1). DAP1 is involved in mediating interferon-gamma-induced cell death . DAPL1 may play a role in the early stages of epithelial differentiation or in apoptosis .
Uncharacterised protein family UPF0489 (UPF0489)
Type: Family

This entry describes a family of uncharacterised proteins found in metazoa.
Akirin (Akirin)
Type: Family

Akirin is a molecular adapter that acts as a bridge between a variety of multiprotein complexes, and which is required for embryonic development and for normal innate immune response. It plays a central role in immune gene expression in insects and mammals, linking the SWI/SNF chromatin-remodelling complex with the transcription factor NFkappaB . Ankirin-2 plays a key role in nuclear protein degradation by promoting import of proteasomes into the nucleus as it directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end, bridging them together and mediating the import of pre-assembled proteasome complexes through the nuclear pore .
Transmembrane protein 138 (TM_138)
Type: Family

This entry represents a family of uncharacterised proteins that have been termed transmembrane protein 138.
Superoxide dismutase (Cu/Zn) / superoxide dismutase copper chaperone (SOD_Cu/Zn_/chaperone)
Type: Family

Superoxide dismutases (SODs) are ubiquitous metalloproteins that prevent damage by oxygen-mediated free radicals by catalysing the dismutation of superoxide into molecular oxygen and hydrogen peroxide . Superoxide is a normal by-product of aerobic respiration and is produced by a number of reactions, including oxidative phosphorylation and photosynthesis. The dismutase enzymes have a very high catalytic efficiency due to the attraction of superoxide to the ions bound at the active site .

There are three forms of superoxide dismutase, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types. The Fe and Mn forms are similar in their primary, secondary and tertiary structures, but are distinct from the Cu/Zn form . Prokaryotes and protists contain Mn, Fe or both types, while most eukaryotic organisms utilise the Cu/Zn type.

This entry represents the superoxide dismutase proteins as well as a related family of copper chaperones for superoxide dismutases. These cytosolic proteins deliver copper to Cu/Zn superoxide dismutases and are vital to their function .
Ragulator complex protein LAMTOR5 (LAMTOR5)
Type: Family

Hepatitis B X-interacting protein (HBXIP, also known as LAMTOR5) was originally recognised for its association with the X protein of hepatitis B virus (HBV) and ability to down-regulate HBV replication . When complexed to the anti-apoptotic protein survivin, HBXIP interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerised APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway . HBXIP is one of the Ragulator components that are required for mTORC1 activation by amino acids . It is also part of the AA (amino acid) sensing machinery in human CD4+ T cells .
Histone deacetylase complex subunit SAP130 (His_deAcase_cplx_SAP130)
Type: Family

Histone acetylation plays a key role in the regulation of gene expression. The chromatin structure and accessibility of genes to transcription factors is regulated by enzymes that acetylate and deacetylate histones. The Sin3A-histone deacetylase (HDAC) co-repressor complex consists of multiple proteins and regulates gene expression by deacetylating histones.

SAP130 (Sin3-associated protein 130) is a component of the histone deacetylase-dependent co-repressor complex mSin3A that acts as a transcriptional repressor. It may function in the assembly and/or enzymatic activity of mSin3A or in mediating interactions between the complex and other regulatory complexes .
Pericentriolar material 1 protein (Pericentriolar_Pcm1)
Type: Family

Pericentriolar material 1 protein is required for centrosome assembly and function. It is essential for the correct localisation of several centrosomal proteins and required to anchor microtubules to the centrosome . It is probably involved in the biogenesis of cilia .
Phorbol-12-myristate-13-acetate-induced protein 1 (Noxa)
Type: Family

Phorbol-12-myristate-13-acetate-induced protein 1, also known as Noxa, is a p53 transcriptional target involved in the response to DNA-damaging agents . Noxa can also be activated by other transcriptional factors, suggesting a broad role in the response to cellular stresses. It has been shown to promote activation of caspases and apoptosis .
Histone deacetylase complex subunit SAP30/SAP30-like (His_deAcase_SAP30/SAP30L)
Type: Family

Histone acetylation plays a key role in the regulation of gene expression. The chromatin structure and accessibility of genes to transcription factors is regulated by enzymes that acetylate and deacetylate histones. The Sin3A-histone deacetylase (HDAC) co-repressor complex consists of multiple proteins and regulates gene expression by deacetylating histones.

This entry includes both Sin3-associated protein 30 (SAP30) and SAP30L, a close homologue of SAP30. Both are able to target Sin3A to the nucleolus .
Claspin (Claspin)
Type: Family

Claspin is an essential protein for the ATR-Chk1-dependent activation of the DNA replication checkpoint response in Xenopus and human cells . DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. It is thought that ATR regulates Claspin phosphorylation in response to DNA damage and replication stress, resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate Chk1 .

This entry represents both claspin and claspin homologues found mainly in Drosophila.
Paralemmin-3 (Paralemmin-3)
Type: Family

Paralemmin-3 is a member of the paralemmin protein family and may function as an adaptor in the LPS- Toll-like receptor 4 signalling .
Inhibitor of nuclear factor kappa-B kinase-interacting protein (Inh_kappa-B_kinase-int)
Type: Family

IKIP (I kappa B kinase interacting protein) is a p53 target gene with proapoptotic function .
Suprabasin (Suprabasin)
Type: Family

Suprabasin (SBN) is expressed in mouse and human differentiating keratinocytes, being involved in epidermal differentiation which may play a role in skin barrier formation . It has been proposed to be a component of the cornified envelope, an essential structure for skin protection . Its exact function is not yet clear; it has been associated with multiple diseases such as cancer and autoimmune disorders . It is a secreted molecule that may induce cellular signalling (AKT, WNT/beta-catenin, and/or p38MAPK signalling) and processes (migration, proliferation, neovascularization apoptosis- and immune-resistance). It contains a repeated sequence GxHH, with no other similar sequence in the human proteome, which suggests an evolutionarily unique and conserved role . It has also been described a FG (Phe-Gly) motif, which is common in scaffold proteins (keratin 1/2/10 and fillagrin-2 in addition to SBSN) .
Mitochondrial import protein TIM15 (Mt_import_TIM15)
Type: Family

Mitochondrial functions rely on the correct transport of resident proteins synthesized in the cytosol to mitochondria. Protein import into mitochondria is mediated by membrane protein complexes, protein translocators, in the outer and inner mitochondrial membranes, in cooperation with their assistant proteins in the cytosol, intermembrane space and matrix. Proteins destined to the mitochondrial matrix cross the outer membrane with the aid of the outer membrane translocator, the tOM40 complex, and then the inner membrane with the aid of the inner membrane translocator, the TIM23 complex, and mitochondrial motor and chaperone (MMC) proteins including mitochondrial heat- shock protein 70 (mtHsp70), and translocase in the inner mitochondrial membrane (Tim)15. Tim15 is also known as zinc finger motif (Zim)17 or mtHsp70 escort protein (Hep)1. Tim15 contains a zinc-finger motif (CXXC and CXXC) of ~100 residues, which has been named DNL after a short C-terminal motif of D(N/H)L .
Adaptor protein Cbl, PTB domain (Cbl_PTB)
Type: Domain

Cbl (Casitas B-lineage lymphoma) is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface.

The N-terminal region of Cbl contains a Cbl-type phosphotyrosine-binding (Cbl-PTB) domain, which is composed of three evolutionarily conserved domains: an N-terminal four-helix bundle (4H) domain, an EF hand-like calcium-binding domain, and a divergent SH2-like domain. The calcium-bound EF-hand wedges between the 4H and SH2 domains, and roughly determines their relative orientation. The Cbl-PTB domain has also been named Cbl N-terminal (Cbl-N) or tyrosine kinase binding (TKB) domain .

The N-terminal 4H domain contains four long α-helices. The C and D helices in this domain pack against the adjacent EF-hand-like domain, and a highly conserved loop connecting the A and B helices contacts the SH2-like domain. The EF-hand motif is similar to classical EF-hand proteins. The SH2-like domain retains the general helix-sheet-helix architecture of the SH2 fold, but lacks the secondary β-sheet, comprising β-strands D', E and F, and also a prominent BG loop .

This entry represents the Cbl-PTB domain.