SII-SWORD/CoKE huggingface dataset:
CD2-associated protein, first SH3 domain (CD2AP_SH3_1)
Type: Domain

CD2AP is a multifunctional adaptor protein involved in membrane trafficking, dynamic actin remodelling and endocytosis . CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. Different biological processes regulated by CD2AP require specific binding partners .

This entry represents the first SH3 domain (SH3A). It binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2 .
CD2-associated protein, second SH3 domain (CD2AP_SH_2)
Type: Domain

CD2AP is a multifunctional adaptor protein involved in membrane trafficking, dynamic actin remodelling and endocytosis . CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. Different biological processes regulated by CD2AP require specific binding partners .

This entry represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site .
CD2-associated protein, third SH3 domain (CD2AP_SH3_3)
Type: Domain

CD2AP is a multifunctional adaptor protein involved in membrane trafficking, dynamic actin remodelling and endocytosis . CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. Different biological processes regulated by CD2AP require specific binding partners .

This entry represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin .
Heterogeneous nuclear ribonucleoprotein U, SPRY domain (SPRY_hnRNP_U)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of heterogeneous nuclear ribonucleoprotein U (hnRNP U) and hnRNP U-like proteins 1 and 2.

hnRNP U contains three conserved domains: a SAF-Box that binds to AT-rich chromosomal region known as a scaffold- or matrix-attachment region (S/MAR), SPRY (Spla and Ryanodine receptor) domain of unknown function, and RGG (arginine-glycine-glycine) RNA-binding domain. hnRNP U is involved in transcription , alternative splicing and inactivation one of the two female X chromosomes . hnRNP U-like proteins 1 and 2 play key roles in cellular responses to double-strand breaks (DSBs) .
MLK1-3, SH3 domain (MLK1-3_SH3)
Type: Domain

MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals .
Ssh4-like, SPRY domain (SPRY_Ssh4-like)
Type: Domain

This entry represents the SPRY domain found in Ssh4 (suppressor of SHR3 null mutation protein 4) and similar proteins. Ssh4 is a component of the endosome-vacuole trafficking pathway that regulates nutrient transport and may be involved in processes determining whether plasma membrane proteins are degraded or routed to the plasma membrane . The SPRY domain in Ssh4 may be involved in cargo recognition, either directly or by combination with other adaptors, possibly leading to a higher selectivity. In yeast, Ssh4 and the homologous protein Ear1 (endosomal adapter of RSP5) recruit Rsp5p, an essential ubiquitin ligase of the Nedd4 family, and assist it in its function at multivesicular bodies by directing the ubiquitylation of specific cargoes .
HECTD4, SPRY domain (SPRY_HECTD4)
Type: Domain

This is the SPRY domain of HECTD4 (HECT domain-containing protein 4). HECTD4 is a probable E3 ubiquitin-protein ligase, as the HECT (Homologous to the E6-AP Carboxyl Terminus) domain has been identified in proteins that belong to a particular E3 ubiquitin-protein ligase family . The role of HECTD4 is not known.
Ran binding protein 9/10, SPRY domain (SPRY_RanBP9/10)
Type: Domain

This SPRY domain is found in Ran binding protein M (RanBPM, also known as RanBP9) and RanBP10.
RanBPM and RanBP10 are non-canonical members of the Ran binding protein family that lack the Ran binding domain and do not associate with Ran GTPase in vivo. RanBPM is a scaffolding protein important for a variety of cellular processes . RanBP10 has been shown to function as a cytosolic guanine exchange factor and microtubule regulator . Both of these proteins contain a SPRY domain, which has been implicated in mediating protein-protein interactions with a variety of targets, including the DEAD-box containing ATP-dependent RNA helicase (DDX-4) . This entry also includes GID complex subunit 1 (glucose-induced degradation-deficient)

, also known as the CTLH (C-terminal to LisH) complex in humans . RanBPM is a crucial component of the GID complex.

The SPRY domain is a ~140-amino-acid protein interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity, or embryonic development . It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. Functionally, SPRY domains mediate critical interactions in diverse pathways: SSB-2 binds Par-4 to regulate apoptosis, RanBPM/SSB-1 interact with c-Met for signalling modulation, and SPSB proteins target iNOS for ubiquitination in immune regulation .

The B30.2 domain was first identified as a protein domain encoded by an exon (named B30-2) in the Homo sapiens class I major histocompatibility complex region , whereas the SPRY domain was first identified in a Dictyostelium discoideum kinase splA and mammalian calcium-release channels ryanodine receptors . B30.2 domain consists of PRY and SPRY subdomains. The SPRY domains (after SPla and the RYanodine Receptor) are shorter at the N terminus than the B30.2 domains. The ~200-residue B30.2/SPRY (for B30.2 and/or SPRY) domain is present in a large number of proteins with diverse individual functions in different biological processes. The B30.2/SPRY domain in these proteins is likely to function through protein-protein interaction .
The N-terminal ~60 residues of B30.2/SPRY domains are poorly conserved and, as a consequence, a new domain name PRY was coined for a group of similar sequence segments N-terminal to the SPRY domains . The B30.2/SPRY domain contains three highly conserved motifs (LDP, WEVE and LDYE) . The B30.2/SPRY domain adopts a highly distorted, compact β-sandwich fold with two additional short β-helices at the N terminus. The β-sandwich of the B30.2/SPRY domain consists of two layers of β-sheets: sheet A composed of eight strands and sheet B composed of seven strands. All the β-strands are in antiparallel arrangement . The 5th β-strand corresponding to WEVE motif . Both the N- and C-terminal ends of the B30.2/SPRY domains in general are close to each other .
SPRY domain-containing protein 3, SPRY domain (SPRYD3_SPRY)
Type: Domain

This is the SPRY domain of SPRY domain-containing protein 3 (SPRYD3). The function of this protein is not known.
Fbxo45, SPRY domain (SPRY_FBXO45)
Type: Domain

Fbxo45 is a novel synaptic E3 and ubiquitin ligase related to the suppressor of cytokine signaling (SOCS) proteins . Fbxo45 induces the degradation of a synaptic vesicle-priming factor Munc13-1 via the SPRY domain, thus playing an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse . F-box motifs are found in proteins that function as the substrate recognition component of SCF E3 complexes .
TRIM75, PRY/SPRY domain (SPRY/PRY_TRIM75)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM75, also known as Gm794. TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and are also known as RBCC proteins . TRIM75 is an antiviral candidate gene within the primate TRIM family . It has not yet been characterised.
TRIM60, PRY/SPRY domain (SPRY/PRY_TRIM60)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM60, which is also known as RING finger protein 33 (RNF33) or 129 (RNF129). TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and are also known as RBCC proteins . It mediates SUMOylation of TAB2 leading to inhibition of NF-kappa-B and MAPK pathways by suppressing the TRAF6/TAB2/TAK1 complex . Based on its expression profile, RNF33 likely plays an important role in the spermatogenesis process, the development of the pre-implantation embryo, and in testicular functions. RNF33 is temporally transcribed in the unfertilized egg and the pre-implantation embryo, and is permanently silenced before the blastocyst stage . Mice experiments have shown that RNF33 associates with the cytoplasmic motor proteins, kinesin-2 family members 3A (KIF3A) and 3B (KIF3B), suggesting possible contribution to cargo movement along the microtubule in the expressed sites .
E3 ubiquitin-protein ligase TRIM58, PRY/SPRY domain (SPRY/PRY_TRIM58)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of Trim58, also known as BIA2. TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region, and are also known as RBCC proteins . Trim58 has been implicated by genome-wide association studies (GWAS) in the regulation of erythrocyte traits, including cell size and number. Trim58 facilitates erythroblast enucleation by inducing proteolytic degradation of the microtubule motor dynein .
Rho guanine nucleotide exchange factor 6, SH3 domain (AlphaPIX_SH3)
Type: Domain

Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP . It acts as a GEF for both Cdc42 and Rac1, and is localized in dendritic spines where it regulates spine morphogenesis . It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans .
Rho guanine nucleotide exchange factor 7, SH3 domain (BetaPIX_SH3)
Type: Domain

Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac1 , and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion .

PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs .

This entry represents the SH3 domain of beta-PIX.
E3 ubiquitin-protein ligase TRIM38, PRY/SPRY domain (SPRY/PRY_TRIM38)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM38, which is also known as RING finger protein 15 (RNF15) or RORET. TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and are also known as RBCC proteins . TRIM38 has been shown to act as a suppressor in TOLL-like receptor (TLR)-mediated interferon (IFN)-beta induction by promoting degradation of TRAF6 and NAP1 through the ubiquitin-proteasome system . Another study has shown that TRIM38 may act as a novel negative regulator for TLR3-mediated IFN-beta signaling by targeting TRIF for degradation . TRIM38 has been identified as a critical negative regulator in TNFalpha- and IL-1beta-triggered activation of NF-kappaB and MAP Kinases (MAPKs); it causes degradation of two essential cellular components, TGFbeta-associated kinase 1 (TAK1)-associating chaperones 2 and 3 (TAB2/3) . The degradation is promoted through a lysosomal-dependent pathway, which requires the C-terminal PRY-SPRY of TRIM38. Enterovirus 71 infection induces degradation of TRIM38, suggesting that TRIM38 may play a role in viral infections .
TRIM27, PRY/SPRY domain (SPRY/PRY_TRIM27)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM27, also known as RING finger protein 76 (RNF76) or RET finger protein (RFP). TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and are also known as RBCC proteins . TRIM27 exhibits either nuclear or cytosolic localization depending on the cell type. TRIM27 negatively regulates nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated signaling by proteasomal degradation of NOD2, suggesting that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases such as Crohn's . High expression of TRIM27 is observed in several human cancers, including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis . Also, TRIM27 forms an oncogenic fusion protein with Ret proto-oncogene. It is involved in different stages of spermatogenesis and its significant expression in male germ cells and seminomas, suggests that TRIM27 may be associated with the regulation of testicular germ cell proliferation and histological-type of germ cell tumors . TRIM27 could also be a predictive marker for chemoresistance in ovarian cancer patients . In the neurotoxin model of Parkinson's disease (PD), deficiency of TRIM27 decreases apoptosis and protects dopaminergic neurons, making TRIM27 an effective potential target during the treatment of PD .
E3 ubiquitin-protein ligase SH3RF2, first SH3 domain (SH3RF2_SH3_1)
Type: Domain

SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation . It may also play a role in cardiac functions together with protein phosphatase 1 . SH3RF2 contains an N-terminal RING finger domain and three SH3 domains.

This entry represents the first SH3 domain, located at the N-terminal half, of SH3RF2.
GDAP2, macro domain (Macro_GDAP2)
Type: Domain

This macro domain is found in proteins similar to human GDAP2, the ganglioside induced differentiation associated protein 2, whose gene is expressed at a higher level in differentiated Neuro2a cells compared with non-differentiated cells . GDAP2 contains an N-terminal macro domain and a C-terminal Sec14p-like lipid binding domain. It is specifically expressed in brain and testis.

The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes .
E3 ubiquitin-protein ligase SH3RF2, second SH3 domain (SH3RF2_SH3_2)
Type: Domain

SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation . It may also play a role in cardiac functions together with protein phosphatase 1 . SH3RF2 contains an N-terminal RING finger domain and three SH3 domains.

This entry represents the second SH3 domain of SH3RF2.
E3 ubiquitin-protein ligase SH3RF1, second SH3 domain (SH3RF1_SH3_2)
Type: Domain

Plenty of SH3 domains protein 1 (POSH1, also known as POSH or E3 ubiquitin-protein ligase SH3RF1) is an SH3 domain containing protein that has been shown to act as an E3 ubiquitin ligase . It belongs to the POSH family, which includes POSH1, POSH2 and POSH3 . It contributes to Rac-induced signal transduction such as JNKs (MAPK8 and MAPK9) activation and induces apoptosis . It plays an essential role in the targeting of HIV-1 Gag to the plasma membrane .

This entry represents the second SH3 domain of SH3RF1.
Core histone macro-H2A, macro domain (Macro_H2A)
Type: Domain

MacroH2A is a variant of the major-type core histone H2A which contains an N-terminal H2A domain and a C-terminal nonhistone macro domain. Histone macroH2A is enriched on the inactive X chromosome of mammalian female cells . It does not bind poly ADP-ribose, but does bind the monomeric SirT1 metabolite O-acetyl-ADP-ribose (OAADPR) with high affinity through its macro domain . In addition, the macro domain of macroH2A associates with histone deacetylases and affects the acetylation status of nucleosomes. MacroH2A-containing nucleosomes are repressive toward transcription .

The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes .
ARHGEF16/ARHGEF26, SH3 domain (ARHGEF16/ARHGEF26_SH3)
Type: Domain

ARHGEF16, also called ephexin-4, acts as a guanine nucleotide exchange factor (GEF) for RhoG, activating it by exchanging bound GDP for free GTP. RhoG is a small GTPase that is a crucial regulator of Rac in migrating cells. ARHGEF16 interacts directly with the ephrin receptor EphA2 and mediates cell migration and invasion in breast cancer cells by activating RhoG . ARHGEF26, also called SGEF (SH3 domain-containing GEF), also activates RhoG. It is highly expressed in liver and may play a role in regulating membrane dynamics . ARHGEF16 and ARHGEF26 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. The SH3 domain of ARHGEF16 also binds to Elmo, and this interaction may relieve the self-inhibitory state of
ARHGEF16 .

This entry represents the SH3 domains of ARHGEF16 and ARHGEF26.
Secretagogin, EF-hand domain (EFh_SCGN)
Type: Domain

Secretagogin (SCGN) is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells . It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2 . SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons . Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker.

SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs . All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologues .
Calbindin-32, EF-hand domain (EFh_CBN)
Type: Domain

Calbindin-32 (CBN), the product of the cbn gene, is a Drosophila homologue to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues .
Sla1, first SH3 domain (Sla1_SH3_1)
Type: Domain

Sla1 is a fungal protein involved in coupling the actin cytoskeleton to the endocytic machinery during endocytosis. It binds to Sla2 (yeast Huntingtin interacting protein-1 HIP1), which plays a role in regulating actin dynamics and endocytosis . It serves as the targeting signal recognition factor for NPFX(1,2)D-mediated endocytosis .

Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1). This entry represents the first SH3 domain of Sla1.
Tepsin, ENTH/VHS domain (ENTH/VHS_tepsin)
Type: Domain

Tepsin (also known as the product of the ENTHD2 or AP4AT gene) is an AP-4 accessory protein. It binds to the beta4-ear domain of AP-4, and is recruited to the trans-Golgi network (TGN) in manner dependent on this interaction . This is the ENTH/VHS domain in tepsin and in A. thaliana protein At3g16270 .

Unlike the other members of the ENTH/ANTH/VHS superfamily, the tepsin ENTH domain lacks helix0, helix8, and a lipid binding pocket. Loss of helix0 precludes formation of a lipid binding pocket and explains why tepsin ENTH domain cannot interact directly with phosphoinositide head groups .
Sorting nexin Vps5, BAR domain (BAR_Vps5)
Type: Domain

Sorting nexins (SNXs) are Phox homology (PX) domain-containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains . The PX-BAR structural unit determines the specific membrane targeting of SNXs .

Vsp5 is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10, as well as other later-Golgi proteins .
Aspartokinase 3, N-terminal (AKIII_YclM_N)
Type: Domain

This is the N-terminal catalytic aspartokinase (AK) domain of the lysine plus threonine-sensitive aspartokinase isoenzyme AKIII, a monofunctional class enzyme found in Bacilli (Bacillus subtilis YclM) and Clostridia species. Aspartokinase is the first enzyme in the aspartate metabolic pathway and catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. In Bacillus subtilis, YclM is reported to be a single polypeptide of 50 kD. The B. subtilis 168 AKIII is induced by lysine and repressed by threonine, and it is synergistically inhibited by lysine and threonine .