Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins 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, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 162287339  33 KLCADEECSHPISMAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRGRLFWGGSVQGGYYGDLAARLGYFPSSIVREDLT 112
Cdd:cd11890    2 KLCADQECSHPISIAVALQDYMAPDCRFIPIQRGQVVYVFSKLKGRGRLFWGGSVQGDYYGEQAARLGYFPSSIVQEDQY 81

                         90
                 ....*....|....*..
gi 162287339 113 LKPGKIDMKTDQWDFYC 129
Cdd:cd11890   82 LKPGKVEVKTDKWDFYC 98

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 162287339  33 KLCADEECSHPISMAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRGRLFWGGSVQGGYYGDLAARLGYFPSSIVREDLT 112
Cdd:cd11890    2 KLCADQECSHPISIAVALQDYMAPDCRFIPIQRGQVVYVFSKLKGRGRLFWGGSVQGDYYGEQAARLGYFPSSIVQEDQY 81

                         90
                 ....*....|....*..
gi 162287339 113 LKPGKIDMKTDQWDFYC 129
Cdd:cd11890   82 LKPGKVEVKTDKWDFYC 98

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 162287339    43 PISMAVALQDYVAPDCRFLTIYRGQVVYVFSKLkgrGRLFWGGSVQGGyygdlaaRLGYFPSSIVR 108
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKS---DDGWWKGRLGRG-------KEGLFPSNYVE 56

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 162287339  33 KLCADEECSHPISMAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRGRLFWGGSVQGGYYGDLAARLGYFPSSIVREDLT 112
Cdd:cd11890    2 KLCADQECSHPISIAVALQDYMAPDCRFIPIQRGQVVYVFSKLKGRGRLFWGGSVQGDYYGEQAARLGYFPSSIVQEDQY 81

                         90
                 ....*....|....*..
gi 162287339 113 LKPGKIDMKTDQWDFYC 129
Cdd:cd11890   82 LKPGKVEVKTDKWDFYC 98

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 162287339  34 LCADEECSHPISMAVALQDYVAPDCRFLTIYRGQVVYVFSKL---KGRGRlFWGGSVQGGYYGDLAARLGYFPSSIVRE 109
Cdd:cd11891    1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLvkeNGAGE-FWSGSVYSERYVDQMGIVGYFPSNLVKE 78

Src Homology 3 domain of Melanoma Inhibitory Activity 3 protein; MIA3, also called TANGO or TANGO1, acts as a tumor suppressor of malignant melanoma. It is downregulated or lost in melanoma cells lines. Unlike other MIA family members, MIA3 is widely expressed except in hematopoietic cells. MIA3 is an ER resident transmembrane protein that is required for the loading of collagen VII into transport vesicles. SNPs in the MIA3 gene have been associated with coronary arterial disease and myocardial infarction. MIA3 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 MIA2. 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 162287339  34 LCADEECSHPISMAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRGRLFWGGSVqggyygdlAARLGYFP 103
Cdd:cd11893    1 RCADEECSMLLCRGKAVKDFTGPDCRFLSFKKGETIYVYYKLSGRRTDLWAGSV--------GFDFGYFP 62

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 162287339  46 MAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRGrlFWGGSVQGgyygdlaaRLGYFPSSIVRED 110
Cdd:cd11978    2 IAIARYDFCARDMRELSLLKGDVVKIYTKMSTNG--WWRGEVNG--------RVGWFPSTYVEED 56

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. 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 162287339  45 SMAVALQDYVAPDCRFLTIYRGQVVYVFSKLKGRgrlfwggsvQGGYYGDLAARLGYFPSSIVRED 110
Cdd:cd11977    1 GTAVARYNFAARDMRELSLREGDVVRIYSRIGGD---------QGWWKGETNGRIGWFPSTYVEEE 57

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. 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 162287339  47 AVALQDYVAPDCRFLTIYRGQVVYVFSKLkgrgrlfwGGSVQGGYYGDLAARLGYFPSSIV 107
Cdd:cd11884    2 VVAVRAYITRDQTLLSFHKGDVIKLLPKE--------GPLDPGWLFGTLDGRSGAFPKEYV 54

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. 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 162287339  48 VALQDYVAPDCRFLTIYRGQVVYVFSKlkgRGRLFWGGSVQGGyygdlaaRLGYFPSSIV 107
Cdd:cd11812    3 VALYDYTANRSDELTIHRGDIIRVLYK---DNDNWWFGSLVNG-------QQGYFPANYV 52