SII-SWORD/CoKE huggingface dataset:
Synaptotagmin-like protein 4/5, C2A domain (SLP-4/5_C2A)
Type: Domain

Synaptotagmin-like proteins (Slps) contain a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains, C2A and C2B . The characteristic feature of the Slp family is the N-terminal domain (referred to as SHD for Slp Homology Domain), which is not found in other C-type tandem C2 proteins . SHD functions as a specific Rab27A/B-binding domain . The C2B domain of Slp4 (also known as Granuphilin) interact with the plasma membrane lipid phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements, type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances, including phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this, including RIM isoforms and some splice variants of piccolo/aczonin and intersectin, which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
TNF receptor-associated factor 3, MATH domain (TRAF3_MATH)
Type: Domain

Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein (MAP) kinase activation and non-canonical nuclear factor-kB signalling . It is a critical regulator of both innate and adaptive immune responses . TRAF3 plays a role in the regulation of B-cell survival , in the regulation of antiviral responses , and in T-cell dependent immune responses . It is required for normal antibody isotype switching from IgM to IgG . Differences in the ubiquitination of TRAF3 are the key to the selective production of type I interferons versus proinflammatory cytokines .

TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal α helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors .
TNF receptor-associated factor 2, MATH domain (TRAF2_MATH)
Type: Domain

TNF receptor-associated factor 2 (TRAF2) regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis .

TRAF2 is heavily regulated by ubiquitin signals. It has E3 ubiquitin-protein ligase activity and promotes K63-linked ubiquitination of target proteins. Alternatively, TRAF2 may be required for recruiting other E3 ligases, such as A20, to help processing and turnover. Furthermore, TRAF2 is regulated by both K63 and K48 type ubiquitin chains. K63 linkage may be mediated by TRAF2 auto-ubiquitination, and is required for TRAF2 activation. c-IAPl and Siah2 are known E3 ligases that can K48-ubiquitinate TRAF2 to target it for proteasome-dependent degradation . TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain.

The TRAF domain can be divided into a more divergent N-terminal α helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors .
TNF receptor-associated factor 1, MATH domain (TRAF1_MATH)
Type: Domain

TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis . TRAF1 is unique among TRAF proteins in that it lacks a RING domain found in the N-terminal regions of other TRAFs . The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14 .

TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events . TRAF1 contains one zinc finger and one TRAF domain.

The TRAF domain can be divided into a more divergent N-terminal α helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors .
TNF receptor-associated factor 4, MATH domain (TRAF4_MATH)
Type: Domain

TNF receptor-associated factor 4 (TRAF4) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. TRAF4 plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. It regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. TRAF4 modulates TRAF6 functions . In mouse, it has been shown to be required for normal skeleton development, and for normal development of the respiratory tract . TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain.

The TRAF domain can be divided into a more divergent N-terminal α helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors .
TNF receptor-associated factor 6, MATH domain (TRAF6_MATH)
Type: Domain

TNF receptor-associated factor 6 (TRAF6) regulates a diverse array of processes, including adaptive immunity, innate immunity, bone metabolism and tissue development. It is a unique member of the TRAF family of adaptor proteins in that it is involved in both the TNF receptor superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily signal transduction pathways . TRAF6 possesses ubiquitin ligase activity that controls the activation of IKK and NF-kappaB . TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain.

The TRAF domain can be divided into a more divergent N-terminal α helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors .
Rho-associated protein kinase 1, HR1 (ROCK1_HR1)
Type: Domain

Rho-associated protein kinases (ROCKs) were originally identified as small GTPase Rho effectors. Later, ROCKs were found actively phosphorylating many actin-binding proteins and intermediate filament proteins to modulate their functions . Two ROCK isoforms have been identified:
ROCK1 (ROKb, p160ROCK) and ROCK2. As major downstream effectors of the small GTPase RhoA, they regulate cellular contraction, motility, morphology, polarity, cell division, and gene expression .

This entry represents the HR1 domain found in Rho-associated protein kinase 1 (ROCK1), which is essential for the formation of stress fibres . ROCK1 contains an N-terminal extension, a catalytic kinase domain, and a long C-terminal extension, which contains a Rho-binding HR1 domain and a pleckstrin homology (PH) domain. ROCK1 is auto-inhibited by HR1 and PH domains interacting with the catalytic domain. HR1 domains are anti-parallel coiled-coil (ACC) domains that bind small GTPases from the Rho family .
Rho-associated protein kinase 2, HR1 domain (ROCK2_HR1)
Type: Domain

Rho-associated protein kinases (ROCKs) were originally identified as small GTPase Rho effectors. Later, ROCKs were found actively phosphorylating many actin-binding proteins and intermediate filament proteins to modulate their functions . Two ROCK isoforms have been identified:
ROCK1 (ROKb, p160ROCK) and ROCK2. As major downstream effectors of the small GTPase RhoA, they regulate cellular contraction, motility, morphology, polarity, cell division, and gene expression .

This entry represents the HR1 domain found in Rho-associated protein kinase 2 (ROCK2), which is essential for the formation of stress fibres . ROCK2 contains an N-terminal extension, a catalytic kinase domain, and a long C-terminal extension, which contains a Rho-binding HR1 domain and a pleckstrin homology (PH) domain. ROCK2 is auto-inhibited by HR1 and PH domains interacting with the catalytic domain. HR1 domains are anti-parallel coiled-coil (ACC) domains that bind small GTPases from the Rho family .
Protein kinase C-like, HR1 domain (PKC-like_HR1)
Type: Domain

This entry represents the second HR1 domain found in fungal PKC-like proteins including Pkc1p from Saccharomyces cerevisiae, and Pck1p and Pck2p from Schizosaccharomyces pombe. The yeast PKC-like proteins play a critical role in regulating cell wall biosynthesis and maintaining cell wall integrity . They contain two HR1 domains, C2 and C1 domains, and a kinase domain. HR1 domains are anti-parallel coiled-coil (ACC) domains that bind small GTPases from the Rho family . The HR1 domains of Pck1p and Pck2p interact with GTP-bound Rho1p and Rho2p .
Serine/threonine-protein kinase N, first HR1 domain (PKN_HR1_1)
Type: Domain

PKN, also called Protein-kinase C-related kinase (PRK), is a serine/threonine protein kinase that can be activated by the small GTPase Rho, and by fatty acids such as arachidonic and linoleic acids. It is involved in many biological processes including cytoskeletal regulation, cell adhesion, vesicle transport, glucose transport, regulation of meiotic maturation and embryonic cell cycles, signaling to the nucleus, and tumorigenesis . In some vertebrates, there are three PKN isoforms from different genes (designated PKN1, PKN2, and PKN3), which show different enzymatic properties, tissue distribution, and varied functions . PKN proteins contain three HR1 domains, a C2 domain, and a kinase domain. This entry represents the first HR1 domain of PKN. HR1 domains are anti-parallel coiled-coil (ACC) domains that bind small GTPases from the Rho family .
Post-transcriptional regulator MKT1, H3TH domain (MKT1_H3TH)
Type: Domain

Mkt1 interacts with the Poly(A)-binding protein associated factor, Pbp1, and is present at the 3' end of RNA transcripts during translation. The Mkt1-Pbp1 complex is involved in the post-transcriptional regulation of HO endonuclease expression .
Exonuclease-1, H3TH domain (EXO1_H3TH)
Type: Domain

Exonuclease-1 (EXO1) is a 5'-3' exonuclease that functions in DNA mismatch repair (MMR), double-strand break repair, replication and recombination . It also possesses a flap-endonuclease activity .
Yen1, H3TH domain (Yen1_H3TH)
Type: Domain

Yen1 is an endonuclease which resolves Holliday junctions by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated .

This entry represents the H3TH domain of Yen1. The H3TH domain has an extended loop with at least three turns between the first two helices, and only three of the four helices appear to be conserved. Together with the helical arch and network of amino acids interacting with metal binding ions, the H3TH region defines a positively charged active-site DNA-binding groove in structure-specific 5' nucleases .
Serine/threonine-protein kinase N1, second HR1 domain (PKN1_HR1_2)
Type: Domain

PKN1 is a serine/threonine protein kinase activated by the Rho family of small GTPases, and by fatty acids such as arachidonic and linoleic acids . It is expressed ubiquitously and is the most abundant PKN isoform in neurons . PKN1 is implicated in a variety of functions including cytoskeletal reorganization, cardiac cell survival, cell adhesion, and glucose transport, among others . PKN1 contains three HR1 domains, a C2 domain, and a kinase domain.

This entry represents the second HR1 domain of PKN1. HR1 domains are anti-parallel coiled-coil (ACC) domains that bind small GTPases from the Rho family; PKN1 binds the GTPases RhoA, RhoB, and RhoC, and can also interact weakly with Rac .
Hex1, S1 domain (Hex1_S1)
Type: Domain

Hex1 is the major component of the Woronin body in filamentous fungi and it has an essential function in conidia production and secondary metabolism in A. flavus. Hex1 may also play an important role in the invasion of A. flavus to the host. The Woronin body is a dense vesicle and plays a vital role in filamentous fungi cell integrity. When cell damage occurs, Woronin bodies seal the septal pore to prevent further cytoplasmic bleeding. Hex1 protein self-assembles to form the solid core of the Woronin body vesicle. The Hex1 sequence and structure are similar to eukaryotic initiation factor 5A (eIF5A), suggesting they share a common ancestor during evolution . All members of the EF superfamily to which Hex1 belongs, contain an S1 domain, which has been shown to bind RNA or single-stranded DNA and often interacts with the ribosome .
Rrp40, S1 domain (Rrp40_S1)
Type: Domain

Rrp40 is a non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In Saccharomyces cerevisiae, the exosome includes nine core components, six of which are homologous to bacterial RNase PH. These form a hexameric ring structure. The other three subunits (RrP4, Rrp40, and Csl4) contain an S1 RNA binding domain and are part of the "S1 pore structure" .

This entry represents the S1 domain of Rrp40. The S1-like RNA-binding domain has been found in a wide variety of RNA-associated proteins .
KIN17-like protein (KIN17-like)
Type: Family

KIN17 is an essential, highly conserved nuclear protein that functions in DNA replication, DNA repair and cell cycle control .
EDEM3, PA domain (EDEM3_PA)
Type: Domain

EDEM3 is involved in endoplasmic reticulum-associated degradation (ERAD). It accelerates the glycoprotein degradation by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans .

This entry represents the PA (protease associated) domain of EDEM3. The function of this domain is not clear.
PRADC1-like protein, PA domain (PRADC1-like_PA)
Type: Domain

PRADC1 (also known as hPAP21 in human) is a secreted glycoprotein with unknown function . This entry represents the PA (protease-associated) domain of PRADC1.
Transferrin receptor protein 1/2, PA domain (TfR1/2_PA)
Type: Domain

This entry represents the PA domain found in transferrin receptor proteins 1 (TfR1) and 2 (TfR2). The function of the PA domain is not clear.

The transferrin receptor 1 (TfR) is a transmembrane protein that assists iron uptake into vertebrate cells through a cycle of endo- and exocytosis of the iron transport protein transferrin (Tf). TfR binds iron-loaded (diferric) Tf at the cell surface and carries it to the endosome, where the iron dissociates from Tf. The apo-Tf remains bound to TfR until it reaches the cell surface, where apo-Tf is replaced by diferric Tf from the serum to begin the cycle again. The crystal structure of a TfR monomer reveals a 3-domain structure: a protease-like domain that closely resembles carboxy- and amino-peptidases; an apical domain consisting of a β-sandwich; and a helical dimerisation domain. The dimerisation domain consists of a 4-helical bundle that makes contact with each of the three domains in the dimer partner .

In humans, TfR is a homodimeric type II transmembrane protein highly expressed on brain endothelial cells. It may undergo transcytosis at the blood-brain barrier (BBB) to allow entry of iron-bound Transferrin by constitutive endocytosis . The TfR-facilitated transcytosis has been explored to deliver therapeutics into the brain in a noninvasive manner .
Bromodomain adjacent to zinc finger domain protein 1A, bromodomain (Acf1_Bromo)
Type: Domain

Bromo adjacent to zinc finger 1A (also known as ACF1) is the regulatory subunit of the ACF-1 and ACF-5 ISWI chromatin remodeling complexes,
which form ordered nucleosome arrays on chromatin and regulates spacing of nucleosomes using ATP to generate evenly spaced nucleosomes along the chromatin . Bromodomains are 110 amino acid long domains, that are found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine .
Ankyrin repeat and SOCS box protein 7, SOCS box domain (ASB7_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB7.
Ankyrin repeat and SOCS box protein 6, SOCS box domain (ASB6_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB6.
Ankyrin repeat and SOCS box protein 5, SOCS box domain (ASB5_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB5.
Ankyrin repeat and SOCS box protein 3, SOCS box domain (ASB3_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB3.
Ankyrin repeat and SOCS box protein 2, SOCS box domain (ASB2_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB2.
Ankyrin repeat and SOCS box protein 1, SOCS box domain (ASB1_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB1.
Ankyrin repeat and SOCS box protein 8, SOCS box domain (ASB8_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB8.
Ankyrin repeat and SOCS box protein 9/11, SOCS box domain (ASB9/11_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB9 and ASB11.
Ankyrin repeat and SOCS box protein 13, SOCS box domain (ASB13_SOCS)
Type: Domain

ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence . The general function of the SOCS box is the recruitment of the ubiquitin-transferase system . The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 . Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

This entry represents the SOCS box domain of ASB13.
DEP domain-containing mTOR-interacting protein, DEP domain 1 (DEPTOR_DEP_1)
Type: Domain

DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR inhibitor that plays pivotal roles in the pathogenesis and progression of many tumours .

This entry represents the first DEP domain of DEPTOR. Its function is not clear.
DEP domain-containing mTOR-interacting protein, DEP domain 2 (DEPTOR_DEP_2)
Type: Domain

DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR inhibitor that plays pivotal roles in the pathogenesis and progression of many tumours .

This entry represents the second DEP domain of DEPTOR. Its function is not clear.
Dip2-like domain (Dip2-like_dom)
Type: Domain

Dip2 proteins show sequence similarity to other members of the adenylate forming enzyme family, including insect luciferase, acetyl CoA ligases and the adenylation domain of nonribosomal peptide synthetases (NRPS) . However, its function may have diverged from other members of the superfamily. In mouse embryo, Dip2 homologue A plays an important role in the development of both vertebrate and invertebrate nervous systems. Dip2A appears to regulate cell growth and the arrangement of cells in organs. Biochemically, Dip2A functions as a receptor of FSTL1, an extracellular glycoprotein, and may play a role as a cardiovascular protective agent .

According to bioinformatics analysis DIP2A is a type I receptor molecule with three domains from the N to the C terminus: the DNA methyltransferase 1 associated protein (DMAP)-binding domain, CaiC, and adenosine monophosphate (AMP)-binding domain. This entry corresponds to the CaiC domain of Dip2. The CaiC domain also binds AMP and is found in acyl CoA synthetases and AMP-acid ligases that are involved in lipid metabolism, secondary metabolite biosynthesis, transport and catabolism .