Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  34 LCADDECVYTLSLARAEDDYNAPDCRFINIKRGDLVYVYSKLIKQEDGGEFWSGSVYSDQYRDQMGLVGYFPSSLVTELH 113
Cdd:cd11891    1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERYVDQMGIVGYFPSNLVKEQT 80

                 ...
gi 148230861 114 VYQ 116
Cdd:cd11891   81 VYK 83

Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  34 LCADDECVYTLSLARAEDDYNAPDCRFINIKRGDLVYVYSKLIKQEDGGEFWSGSVYSDQYRDQMGLVGYFPSSLVTELH 113
Cdd:cd11891    1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERYVDQMGIVGYFPSNLVKEQT 80

                 ...
gi 148230861 114 VYQ 116
Cdd:cd11891   81 VYK 83

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 148230861    47 ARAEDDYNAPDCRFINIKRGDLVYVYSKlikqeDGGEFWSGsvysdqyRDQMGLVGYFPSSLVT 110
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEK-----SDDGWWKG-------RLGRGKEGLFPSNYVE 56

Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  34 LCADDECVYTLSLARAEDDYNAPDCRFINIKRGDLVYVYSKLIKQEDGGEFWSGSVYSDQYRDQMGLVGYFPSSLVTELH 113
Cdd:cd11891    1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERYVDQMGIVGYFPSNLVKEQT 80

                 ...
gi 148230861 114 VYQ 116
Cdd:cd11891   81 VYK 83

Melanoma Inhibitory Activity protein; MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands. It binds peptide ligands with sequence similarity to type III human fibronectin repeats.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  32 KKLCADDECVYTLSLARAEDDYNAPDCRFINIKRGDLVYVYSKLikQEDGGEFWSGSVYSDQYRDQMGLVGYFPSSLVTE 111
Cdd:cd11890    1 KKLCADQECSHPISIAVALQDYMAPDCRFIPIQRGQVVYVFSKL--KGRGRLFWGGSVQGDYYGEQAARLGYFPSSIVQE 78

                         90       100
                 ....*....|....*....|
gi 148230861 112 LHVYQDLTQELPTTDIDFYC 131
Cdd:cd11890   79 DQYLKPGKVEVKTDKWDFYC 98

Src Homology 3 domain of Melanoma Inhibitory Activity 2 protein; MIA2 is expressed specifically in hepatocytes and its expression is controlled by hepatocyte nuclear factor 1 binding sites in the MIA2 promoter. It inhibits the growth and invasion of hepatocellular carcinomas (HCC) and may act as a tumor suppressor. A mutation in MIA2 in mice resulted in reduced cholesterol and triglycerides. Since MIA2 localizes to ER exit sites, it may function as an ER-to-Golgi trafficking protein that regulates lipid metabolism. MIA2 contains an N-terminal SH3-like domain, similar to MIA. It is a member of the recently identified family that also includes MIA, MIAL, and MIA3 (also called TANGO). MIA is a single domain protein that adopts a SH3 domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  35 CADDECVYTLSLARAEDDYNAPDCRFINIKRGDLVYVYSKLI-KQEDggeFWSGSVYSDqyrdqmglVGYFPSSLVTELH 113
Cdd:cd11892    2 CGDPECERLMSRVQAIRDYRGPDCRYLSFKKGDEIIVYYKLSgKRED---LWAGSTGKE--------FGYFPKDAVKVEE 70

                 ..
gi 148230861 114 VY 115
Cdd:cd11892   71 VY 72

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 148230861  47 ARAEDDYNAPDCRFINIKRGDLVYVYSKLIKQedggEFWSGSVYsdqyrdqmGLVGYFPSSLVTE 111
Cdd:cd11830    2 AKARYDFCARDMRELSLKEGDVVKIYNKKGQQ----GWWRGEIN--------GRIGWFPSTYVEE 54

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 148230861  48 RAEDDYNAPDCRFINIKRGDLVYVYSKlikQEDGgeFWSGSVysdqyrdqMGLVGYFPSSLVTE 111
Cdd:cd11823    3 KALYSYTANREDELSLQPGDIIEVHEK---QDDG--WWLGEL--------NGKKGIFPATYVEE 53

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play 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. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 148230861  46 LARAEDDYNAPDCRFINIKRGDLVYVysklIKQEDGGeFWSGSVysdqyrdqMGLVGYFPSSLVTE 111
Cdd:cd11877    1 LVRAKFNFEGTNEDELSFDKGDIITV----TQVVEGG-WWEGTL--------NGKTGWFPSNYVKE 53

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 148230861  46 LARAEDDYNAPDCRFINIKRGDLVYVYSKLikqeDGGEFWSGSVYsdqyrdqmGLVGYFPSSLVTE 111
Cdd:cd11978    2 IAIARYDFCARDMRELSLLKGDVVKIYTKM----STNGWWRGEVN--------GRVGWFPSTYVEE 55

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 148230861  47 ARAEDDYNAPDCRF-INIKRGDLVYVYSKLIKQEDGGEFWSGsvysdqyRDQMGLVGYFPSSLVTE 111
Cdd:cd11771    2 CRALYDFTPENPEMeLSLKKGDIVAVLSKTDPLGRDSEWWKG-------RTRDGRIGWFPSNYVEV 60

Src Homology 3 domain of CASK interacting protein 1; Caskin1 is a multidomain adaptor protein that contains six ankyrin repeats, a single SH3 domain, tandem sterile alpha motif (SAM) domains, and a long disordered proline-rich region. It is expressed at high levels in the brain and is localized in presynaptic regions. It binds to the multidomain scaffolding protein CASK through the CaMK domain in competition with Munc-interacting protein 1 (Mint1). CASK participates in one of two evolutionarily conserved tripartite complexes containing either Mint1 and Velis or Caskin1 and Velis. Caskin1 may play a role in infantile myoclonic epilepsy. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 148230861  48 RAEDDY-NAPDCRFINIKRGDLVYVyskLIKQEDGGefWSGSVYSDqyRDQMGLVGYFPSSLV 109
Cdd:cd12062    4 RALKDYcNNYDLTSLNIKAGDVITV---LEQHPDGR--WKGCIHDN--RTGNDRVGYFPSSLV 59

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 148230861  48 RAEDDYNAPDCRFINIKRGDLVYVYSKLikqeDGGeFWSGSVYSDQYRDQMglvGYFPSS 107
Cdd:cd11883    3 VALYDFTPKSKNQLSFKAGDIIYVLNKD----PSG-WWDGVIISSSGKVKR---GWFPSN 54