C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, 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
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1040698987 6060 GKTVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRTGKTGMLPANYVEAI 6117
Cdd:cd11933      1 GKSFRAMYDYRAADDDEVSFKDGDTIVNVQTIDEGWMYGTVQRTGKTGMLPANYVEAI 58

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 3626 DLPVIVLAKQNADILSDRKYREAWDKDK 3653
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*..
gi 1040698987 4322 DTPEIVRAKKSYELQSDIKYKAEGKKE 4348
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKE 27

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 5872 DTPEMRRVKETQRIISGVKYHQDFEKSK 5899
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987  814 DDPLLVHYMQVAKIQSDKLYKKDYHKAK 841
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 5058 DTPELVRAEQNKNLYSERLYKASFEKNR 5085
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*..
gi 1040698987 4919 TPILDHARSMKVVYSEKKYKEQYEKMK 4945
Cdd:pfam00880    2 TPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 3249 DDPLIVLAMNSAKIASDALYKKDFNKSK 3276
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 4113 DRPEIVLAKVNAFNLSDLKYKESFNLEK 4140
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 1302 DDPLLVHYMQVAKMQSERNYKKDYHKSK 1329
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987   138 YLLPPDAPELVLAVKNAANYSKKLYTEVWDE 168
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987    68 YLISADTPEMIRIKKAQEQLSEVKYRMEGLK 98
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, 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
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1040698987 6060 GKTVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRTGKTGMLPANYVEAI 6117
Cdd:cd11933      1 GKSFRAMYDYRAADDDEVSFKDGDTIVNVQTIDEGWMYGTVQRTGKTGMLPANYVEAI 58

Variant SH3 domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1040698987 6065 AMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGtvQRTGKTGMLPANYVE 6115
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEESEDGWWEG--INTGRTGLVPANYVE 49

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987  5614 YHMIPDTPEQLHHKEASELQSHVKYKEKYEK 5644
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987  570 DDPKIMHSVHVAKIQSEREYKKDYEKMK 597
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987  3621 FTSAVDLPVIVLAKQNADILSDRKYREAWDK 3651
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 5872 DTPEMRRVKETQRIISGVKYHQDFEKSK 5899
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987  814 DDPLLVHYMQVAKIQSDKLYKKDYHKAK 841
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20
                    ....*....|....*....|....*.
gi 1040698987  4322 DTPEIVRAKKSYELQSDIKYKAEGKK 4347
Cdd:smart00227    6 DTPEILLAKKNQKLISDVKYKEDYEK 31

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 5058 DTPELVRAEQNKNLYSERLYKASFEKNR 5085
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*..
gi 1040698987 4919 TPILDHARSMKVVYSEKKYKEQYEKMK 4945
Cdd:pfam00880    2 TPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 3249 DDPLIVLAMNSAKIASDALYKKDFNKSK 3276
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 4428 DSHALAHAKQQKVILSNVKYKEDYEKFK 4455
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*..
gi 1040698987 1472 DNPEIILAKANALNMSQKLYKAGLEEM 1498
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKE 27

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*...
gi 1040698987 1546 DDPLLVHYMQVAKMQSERNYKKDYHKSK 1573
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEKEK 28

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987   809 FRSIQDDPLLVHYMQVAKIQSDKLYKKDYHK 839
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987   138 YLLPPDAPELVLAVKNAANYSKKLYTEVWDE 168
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20
                    ....*....|....*....|....*....
gi 1040698987   567 SIKDDPKIMHSVHVAKIQSEREYKKDYEK 595
Cdd:smart00227    3 SVPDTPEILLAKKNQKLISDVKYKEDYEK 31

The Nebulin repeat is present also in Las1; Tandem arrays of these repeats are known to bind actin.

                            10        20        30
                    ....*....|....*....|....*....|.
gi 1040698987    68 YLISADTPEMIRIKKAQEQLSEVKYRMEGLK 98
Cdd:smart00227    1 YTSVPDTPEILLAKKNQKLISDVKYKEDYEK 31

Nebulin repeat;

                           10        20
                   ....*....|....*....|....*.
gi 1040698987  949 DTPVMEQAKLNAQQLSDRLYKASGEK 974
Cdd:pfam00880    1 DTPEIVHAKKNAKLQSDVKYKEDYEK 26

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, 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
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1040698987 6060 GKTVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRTGKTGMLPANYVEAI 6117
Cdd:cd11933      1 GKSFRAMYDYRAADDDEVSFKDGDTIVNVQTIDEGWMYGTVQRTGKTGMLPANYVEAI 58

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, 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
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1040698987 6059 TGKTVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRTGKTGMLPANYVEAI 6117
Cdd:cd11934      1 GGKRYRAVYDYNAADEDEVSFQDGDTIVNVQQIDDGWMYGTVERTGDTGMLPANYVEAI 59

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrTGKTGMLPANYVE 6115
Cdd:cd11960      1 RARALYDYQAADDTEISFDPGDIITDIEQIDEGWWRGTGP-DGTYGLFPANYVE 53

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGtVQRTGKTGMLPANYVE 6115
Cdd:cd11819      1 RAKALYDYQAAEDNEISFVEGDIITQIEQIDEGWWLG-VNAKGQKGLFPANYVE 53

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. 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
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVEA 6116
Cdd:cd11959      1 TAVALYDYQAADDDEISFDPDDIITNIEMIDEGWWRGVCR--GKYGLFPANYVEL 53

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6063 VRAMYDYAAADSDEVSFKDGDVIVNVQSIDE-GWMYGtvQRTGKTGMLPANYVE 6115
Cdd:cd11843      2 VRALYDYEGQESDELSFKAGDILTKLEEEDEqGWCKG--RLDGRVGLYPANYVE 53

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11961      1 WAKALYDYDAAEDNELSFFENDKIINIEFVDDDWWLGECH--GSRGLFPSNYVE 52

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. 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. CIN85 SH3A has also been shown to bind ubiquitin. 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11873      1 EVIVEFDYDAEEPDELTLKVGDIITNVKKMEEGWWEGTLN--GKRGMFPDNFVK 52

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. 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
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1040698987 6065 AMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd12073      5 ALYDYQGEGDDEISFDPQETITDIEMVDEGWWKGTCH--GHRGLFPANYVE 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
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11877      1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLN--GKTGWFPSNYVK 52

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. 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
                   ....*....|....*....|....*....|....*....|....*....|
gi 1040698987 6064 RAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANY 6113
Cdd:cd11818      3 RALYDFTGENEDELSFKAGDIITELESIDEEWMSGELR--GKSGIFPKNF 50

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically 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
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1040698987 6063 VRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11805      2 VQALYDFNPQEPGELEFRRGDIITVLDSSDPDWWKGELR--GRVGIFPANYVQ 52

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. 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.

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gi 1040698987 6063 VRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVEA 6116
Cdd:cd11772      2 FRALYDYEAQHPDELSFEEGDLLYISDKSDPNWWKATCG--GKTGLIPSNYVEE 53

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.

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gi 1040698987 6064 RAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11823      3 KALYSYTANREDELSLQPGDIIEVHEKQDDGWWLGELN--GKKGIFPATYVE 52

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing proteins, also called TULA (T cell Ubiquitin LigAnd) family of proteins; UBASH3 or TULA proteins are also referred to as Suppressor of T cell receptor Signaling (STS) proteins. They contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. In some vertebrates, there are two TULA family proteins, called UBASH3A (also called TULA or STS-2) and UBASH3B (also called TULA-2 or STS-1), which show partly overlapping as well as distinct functions. UBASH3B is widely expressed while UBASH3A is only found in lymphoid cells. UBASH3A facilitates apoptosis induced in T cells through its interaction with the apoptosis-inducing factor AIF. UBASH3B is an active phosphatase while UBASH3A is not. 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.

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gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIV----NVQSIDEGWMYGTVQRTGKTGMLPANYVE 6115
Cdd:cd11791      1 VLRVLYPYTPQEEDELELVPGDYIYvspeELDSSSDGWVEGTSWLTGCSGLLPENYTE 58

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. 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.

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gi 1040698987 6064 RAMYDYAAADSDEVSFKDGDVIV--NVQSIDEGWMYGTVQrtGKTGMLPANYVEA 6116
Cdd:cd11836      3 RALYAFEARNPDEISFQPGDIIQvdESQVAEPGWLAGELK--GKTGWFPANYVEK 55

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). 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.

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gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11827      1 QCKALYAYDAQDTDELSFNEGDIIEILKEDPSGWWTGRLR--GKEGLFPGNYVE 52

Src Homology 3 domain of Ras GTPase-Activating Protein 1; RasGAP, also called Ras p21 protein activator, RASA1, or p120RasGAP, is part of the GAP1 family of GTPase-activating proteins. It is a 120kD cytosolic protein containing an SH3 domain flanked by two SH2 domains at the N-terminal end, a pleckstrin homology (PH) domain, a calcium dependent phospholipid binding domain (CaLB/C2), and a C-terminal catalytic GAP domain. It stimulates the GTPase activity of normal RAS p21. It acts as a positive effector of Ras in tumor cells. It also functions as a regulator downstream of tyrosine receptors such as those of PDGF, EGF, ephrin, and insulin, among others. The SH3 domain of RasGAP is unable to bind proline-rich sequences but have been shown to interact with protein partners such as the G3BP protein, Aurora kinases, and the Calpain small subunit 1. The RasGAP SH3 domain is necessary for the downstream signaling of Ras and it also influences Rho-mediated cytoskeletal reorganization. SH3 domains are protein interaction domains that typically 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.

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gi 1040698987 6061 KTVRAMYDY-AAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRTGKTGMLPANYVEAI 6117
Cdd:cd11788      2 RRVRAILPYnKVPDTDELSFQKGDIFVVHNELEDGWLWVTSLRTGESGLVFRDLVEEL 59

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. 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.

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gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDV--IVNVQSIDEGWMYGTVQrtGKTGMLPANYVE 6115
Cdd:cd11875      1 KARVLFDYEAENEDELTLREGDIvtILSKDCEDKGWWKGELN--GKRGVFPDNFVE 54

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing protein B; UBASH3B, also called Suppressor of T cell receptor Signaling (STS)-1 or T cell Ubiquitin LigAnd (TULA)-2 is an active phosphatase that is expressed ubiquitously. The phosphatase activity of UBASH3B is essential for its roles in the suppression of TCR signaling and the regulation of EGFR. It also interacts with Syk and functions as a negative regulator of platelet glycoprotein VI signaling. TULA proteins contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. 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.

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gi 1040698987 6061 KTVRAMYDYAAADSDEVSFKDGDVI----VNVQSIDEGWMYGTVQRTGKTGMLPANYV 6114
Cdd:cd11936      2 ETLQVIYPYTPQNDDELELVPGDYIfmspMEQTSTSEGWIYGTSLTTGCSGLLPENYI 59

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, 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.

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gi 1040698987 6064 RAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMygTVQRTGKTGMLPANYVE 6115
Cdd:cd11824      3 SVLYDYTAQEDDELSISKGDVVAVIEKGEDGWW--TVERNGQKGLVPGTYLE 52

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. 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.

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gi 1040698987 6063 VRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQRtgKTGMLPANYVEA 6116
Cdd:cd11820      3 VRALYDFEAAEDNELTFKAGEIITVLDDSDPNWWKGSNHR--GEGLFPANFVTA 54

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically 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.

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gi 1040698987 6062 TVRAMYDYAAADSDEVSFKDGDVIVNVQSIDEGWMYGTVQrtGKTGMLPANYVEA 6116
Cdd:cd11949      1 YVQALFDFDPQEDGELGFRRGDFIEVMDNSDPNWWKGACH--GQTGMFPRNYVTP 53