SII-SWORD/CoKE huggingface dataset:
Tyrosine-protein kinase Lyn, SH3 domain (Lyn_SH3)
Type: Domain

Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR . It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 . Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules .

Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction .
Lck, SH3 domain (Lck_SH3)
Type: Domain

Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling . Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events . In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling .

Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction .
Fyn/Yrk, SH3 domain (Fyn/Yrk_SH3)
Type: Domain

Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn is involved in the control of cell growth and is required in diverse pathways, including T and B cell receptor signalling, integrin-mediated signalling, growth factor and cytokine receptor signalling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilisation, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells . In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases . Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury .

Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction .
Tyrosine-protein kinase Yes, SH3 domain (Yes_SH3)
Type: Domain

Yes kinase (also known as c-Yes) is a member of the Src family of nonreceptor tyrosine kinases . It is involved in the regulation of cell division, differentiation, survival, motility, adhesion, spreading and vesicular transport . It plays an important role in epiboly during early development in zebrafish . Yes kinase contains an SH4 motif responsible for membrane localization, a Unique domain, followed by SH3 and SH2 domains, the protein tyrosine kinases or SH1 domain, and a carboxy terminal regulatory region .

This entry represents the SH3 domain of Yes tyrosine kinase.
TRIM1, PRY/SPRY domain (SPRY/PRY_TRIM1)
Type: Domain

This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM1 (also known as MID2 or midline 2). MID2 and its close homologue, TRIM18 (also known as MID1), both contain a B30.2-like domain at their C terminus and a single fibronectin type III (FN3) motif between it and their N-terminal RBCC domain. Mid1 and Mid2 are ubiquitin ligases that regulate microtubule dynamics and whose mutation is associated with X-linked developmental disorders. Mid2 regulates cell division through the ubiquitination of astrin on K409, which is critical for its degradation and proper cytokinesis .
RIMS-binding protein, second SH3 domain (RIM-BP_SH3_2)
Type: Domain

RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2 . RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3 . RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery . RIM-BPs contain three SH3 domains (

) and two to three fibronectin III repeats (

). Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3 . RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis . The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits .

This entry represents the second SH3 domain of RBPs.
SPRY domain-containing SOCS box protein 3, SPRY domain (SPRY_SPSB3)
Type: Domain

The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein-interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor . This entry represents the the SPRY domain of SPSB3.
RIMS-binding protein, third SH3 domain (RIM-BP_SH3_3)
Type: Domain

RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2 . RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3 . RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery . RIM-BPs contain three SH3 domains (

) and two to three fibronectin III repeats (

). Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3 . RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis . The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits .

This entry represents the third SH3 domain of RBPs.
Neutrophil cytosol factor 1, first SH3 domain (NCF1_SH3_1)
Type: Domain

Neutrophil cytosol factor 1 (also known as p47phox, or NCF1) is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation . It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR).

This entry represents the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase .
Neutrophil cytosol factor 1, second SH3 domain (NCF1_SH3_2)
Type: Domain

Neutrophil cytosol factor 1 (also known as p47phox, or NCF1) is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation . It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR).

This entry represents the second SH3 domain (or C-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase .
NADPH oxidase organiser 1, second SH3 domain (NoxO1_SH3_2)
Type: Domain

Nox Organizing protein 1 (NoxO1) is a critical regulator of enzyme kinetics of the nonphagocytic NADPH oxidase Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide . NoxO1 is involved in targeting activator subunits (such as NoxA1) to Nox1. It is co-localized with Nox1 in the membranes of resting cells and directs the subcellular localization of Nox1 . NoxO1 contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), and a C-terminal proline-rich region (PRR).

This entry represents the second SH3 domain (or C-SH3) of NoxO1. The tandem SH3 domains of NoxO1 interact with the PRR of p22phox, which also complexes with Nox1 .
Disks Large homologue 2, SH3 domain (DLG2_SH3)
Type: Domain

DLG2 (also known as PSD-93) is a scaffolding protein that clusters at synapses and plays an important role in synaptic development and plasticity. The DLG2 delta isoform binds inwardly rectifying potassium Kir2 channels, which determine resting membrane potential in neurons. It regulates the spatial and temporal distribution of Kir2 channels within neuronal membranes . DLG2 is a member of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterised by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain . DLG2 contains three PDZ domains .
Voltage-dependent L-type calcium channel subunit beta-3, SH3 domain (CACNB3_SH3)
Type: Domain

The beta4 subunit of voltage-dependent calcium channels (Ca(V)s) is one of four beta subunits present in vertebrates. It is highly expressed in the brain, predominantly in the cerebellum .

This entry represents the SH3 domain of the subunit beta-3.
Ryanodine receptor, SPRY domain 1 (SPRY1_RyR)
Type: Domain

This SPRY domain is the first of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR) . There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3 . The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs . The first domain may be involved in RyR2 dimerization .
Ryanodine receptor, SPRY domain 3 (SPRY3_RyR)
Type: Domain

This SPRY domain is the third of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR) . There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3 . The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this third SPRY domain of the RyRs .
Disks Large homologue 3, SH3 domain (DLG3_SH3)
Type: Domain

DLG3 (discs large homologue 3), also called synapse-associated protein 102 (SAP102), is a scaffolding protein that clusters at synapses and plays an important role in synaptic development and plasticity . It associates with GluN2 subunits of NMDA receptors, particularly GluN2B, which is the dominant subunit in cortical neurones during early development . Mutations in DLG3 are associated with nonsyndromic X-linked mental retardation in humans . DLG3 is a member of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterised by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG3 contains three PDZ domains .

This entry represents the SH3 domain of DLG3.
Ryanodine receptor, SPRY domain 2 (SPRY2_RyR)
Type: Domain

This SPRY domain (SPRY2) is the second of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, The SPRY2 domain has been shown to bind to the dihydropryidine receptor (DHPR) II-III loop and the ASI region of RyR1 .
Src kinase-associated phosphoprotein 1, SH3 domain (SKAP1_SH3)
Type: Domain

SKAP1 (also known as SKAP55) is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages . Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP .
SPRY domain-containing protein 7 (SPRYD7)
Type: Family

This family contains SPRY domain-containing protein 7 (also known as SPRY domain-containing protein 7, CLL deletion region gene 6 protein homologue, CLLD6 or chronic lymphocytic leukemia deletion region gene 6 protein homologue). In humans, CLLD6 is highly expressed in heart, skeletal muscle, and testis as well as cancer cell lines. It also has cross-species conservation, suggesting that it is likely to carry out important cellular processes .
Dedicator of cytokinesis 3, SH3 domain (DOCK3_SH3)
Type: Domain

DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane . DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) . All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker).

This entry represents the SH3 domain found in DOCK3, which has been linked to Alzheimer's disease due to its interaction with presenilin proteins and ability to stimulate Tau/MAPT phosphorylation .
HERC1, SPRY domain (SPRY_HERC1)
Type: Domain

This SPRY domain is found in the HERC1, a large protein related to chromosome condensation regulator RCC1. It is widely expressed in many tissues, playing an important role in intracellular membrane trafficking in the cytoplasm as well as Golgi apparatus . It is both a ubiquitin-protein ligase and a guanine nucleotide exchange factor for ARF and Rab family GTPases. Like other HERC proteins, HERC1 also interacts with tuberous sclerosis 2 (TSC2, tuberin), which suppresses cell growth, and results in the destabilization of TSC2 . HERC1 is essential for neurotransmitter release and neuronal activity . Mutations in HERC1 lead to syndromic intellectual disability .
Dedicator of cytokinesis 4, SH3 domain (DOCK4_SH3)
Type: Domain

DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane . DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) . All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker).

DOCK4 is an atypical guanine nucleotide exchange factor (GEF) that lacks the conventional Dbl homology (DH) domain. It activates small GTPases by exchanging bound GDP for free GTP. It plays a role in regulating dendritic growth and branching in hippocampal neurons, where it is highly expressed. It may also regulate spine morphology and synapse formation and has been linked to autism, dyslexia, and schizophrenia . It also plays a critical role in mediating TGF-beta's prometastatic effects in lung cancer .

This entry represents the SH3 domain found in DOCK4.
SH3 domain-containing kinase-binding protein 1, first SH3 domain (CIN85_SH3_1)
Type: Domain

CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins . It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others . CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions.

This entry represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2 .
SH3 domain-containing kinase-binding protein 1, second SH3 domain (CIN85_SH3_2)
Type: Domain

CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins . It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others . CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions.

This entry represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin .
SH3 domain-containing kinase-binding protein 1, third SH3 domain (CIN85_SH3_3)
Type: Domain

CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins . It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others . CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions.

This entry represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin .
Ring finger protein 123, SPRY domain (SPRY_RNF123)
Type: Domain

This SPRY domain is found at the N terminus of RING finger protein 123 (also known as E3 ubiquitin-protein ligase RNF123, KPC1). The ring finger domain motif is present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RNF123 displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor p27 (Kip1) and p105 and inhibits tumor growth via regulation of p50-dependent tumor suppressor genes .

Proteins containing this domain also include AtKPC1 from Arabidopsis. AtKPC1 is an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of KRP1 and KRP2 .
RING finger and SPRY domain-containing protein 1, SPRY domain (SPRY_RSPRY1)
Type: Domain

This SPRY domain is found at the N terminus of RING finger domains which are present in a variety of functionally distinct proteins and are known to be involved in protein-protein and protein-DNA interactions. The RING-finger domain is a type of Zn-finger that binds two Zn atoms.

The role of RSPRY1 (RING finger and SPRY domain-containing protein 1) is not known, but it may have a role in bone development. Mutations in RSPRY1 cause skeletal dysplasia .