The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. Mutations in BAR containing proteins have been linked to diseases and their inactivation in cells leads to altered membrane dynamics. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysins and endophilins, among others. BAR domains are also frequently found alongside domains that determine lipid specificity, such as the Pleckstrin Homology (PH) and Phox Homology (PX) domains which are present in beta centaurins (ACAPs and ASAPs) and sorting nexins, respectively. A FES-CIP4 Homology (FCH) domain together with a coiled coil region is called the F-BAR domain and is present in Pombe/Cdc15 homology (PCH) family proteins, which include Fes/Fes tyrosine kinases, PACSIN or syndapin, CIP4-like proteins, and srGAPs, among others. The Inverse (I)-BAR or IRSp53/MIM homology Domain (IMD) is found in multi-domain proteins, such as IRSp53 and MIM, that act as scaffolding proteins and transducers of a variety of signaling pathways that link membrane dynamics and the underlying actin cytoskeleton. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The I-BAR domain induces membrane protrusions in the opposite direction compared to classical BAR and F-BAR domains, which produce membrane invaginations. BAR domains that also serve as protein interaction domains include those of arfaptin and OPHN1-like proteins, among others, which bind to Rac and Rho GAP domains, respectively.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  16 HTHTDQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREWSGAPSEEQKDSRNVWAVWRSYLEGVI 95
Cdd:cd07654    1 LRHLEQLSKLQAKHQTECDLLEDIRTYSQKKAAIEREYGQALQKLASQFLKREWPGSGELKPEDDRSGYTVWGAWLEGLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  96 KVSQSRINGCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRKTYQEAEQTAQTVREKADM-EAK 174
Cdd:cd07654   81 AVAQSRQNRCEAYRRYISEPAKTGRSAKEQQLKKCTEQLQRAQAEVQQTVRELSKSRKTYFEREQVAHLAREKAADvQAR 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781 175 YVKT-----------QSVSVTLQSEESKCE--------DY-----------------------HVLDGSFYDHVQSFLIS 212
Cdd:cd07654  161 EARSdlsifqsrtslQKASVKLSARKAECSskataarnDYllnlaatnahqdryyqtdlpaiiKALDGELYDHLKDFLIS 240

                        250       260
                 ....*....|....*....|....
gi 966715781 213 LCQTELETSQSIQDTFQCLLETSS 236
Cdd:cd07654  241 LSHTELETAQVIQETFQRLLETSS 264

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 966715781 535 RALYAYEAQTEDELSFPEGAVICILSKHNQEDDGFWEGEFNGAVGVFPAVLVED 588
Cdd:cd11894    3 KALYDYEGQTDDELSFPEGAIIRILNKENQDDDGFWEGEFNGRIGVFPSVLVEE 56

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH and double SH3 domains proteins (FCHSD); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of FCH and double SH3 domain (FCHSD) proteins, so named as they contain an N-terminal F-BAR domain and two SH3 domains at the C-terminus. Vertebrates harbor two subfamily members, FCHSD1 and FCHSD2, which have been characterized only in silico. Their biological function is still unknown. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  16 HTHTDQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREWSGAPSEEQKDSRNVWAVWRSYLEGVI 95
Cdd:cd07654    1 LRHLEQLSKLQAKHQTECDLLEDIRTYSQKKAAIEREYGQALQKLASQFLKREWPGSGELKPEDDRSGYTVWGAWLEGLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  96 KVSQSRINGCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRKTYQEAEQTAQTVREKADM-EAK 174
Cdd:cd07654   81 AVAQSRQNRCEAYRRYISEPAKTGRSAKEQQLKKCTEQLQRAQAEVQQTVRELSKSRKTYFEREQVAHLAREKAADvQAR 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781 175 YVKT-----------QSVSVTLQSEESKCE--------DY-----------------------HVLDGSFYDHVQSFLIS 212
Cdd:cd07654  161 EARSdlsifqsrtslQKASVKLSARKAECSskataarnDYllnlaatnahqdryyqtdlpaiiKALDGELYDHLKDFLIS 240

                        250       260
                 ....*....|....*....|....
gi 966715781 213 LCQTELETSQSIQDTFQCLLETSS 236
Cdd:cd07654  241 LSHTELETAQVIQETFQRLLETSS 264

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. 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 966715781 535 RALYAYEAQTEDELSFPEGAVICILSKHNQEDDGFWEGEFNGAVGVFPAVLVED 588
Cdd:cd11894    3 KALYDYEGQTDDELSFPEGAIIRILNKENQDDDGFWEGEFNGRIGVFPSVLVEE 56

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
                   ....*....|....*....|....*....|....*....|....*....|.
gi 966715781   428 VLYGYQASQPDELTIQEQEILELIDDGDmEDWVKARNRAGQVGYVPEKYLQ 478
Cdd:smart00326   7 ALYDYTAQDPDELSFKKGDIITVLEKSD-DGWWKGRLGRGKEGLFPSNYVE 56

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 966715781  428 VLYGYQASQPDELTIQEQEILELIDDGDmEDWVKARNRAGQVGYVP 473
Cdd:pfam00018   2 ALYDYTAQEPDELSFKKGDIIIVLEKSE-DGWWKGRNKGGKEGLIP 46

Fes/CIP4 homology domain; Alignment extended from original report. Highly alpha-helical. Also known as the RAEYL motif or the S. pombe Cdc15 N-terminal domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781    19 TDQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREwsgAPSEEQKDSRNVWAVWRSYLEGVIKVS 98
Cdd:smart00055   8 DDGFEALLSRLKNGLRLLEDLKKFMRERAKIEEEYAKKLQKLSKKLRAVR---DTEPEYGSLSKAWEVLLSETDALAKQH 84

                   ..
gi 966715781    99 QS 100
Cdd:smart00055  85 LE 86

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH and double SH3 domains proteins (FCHSD); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of FCH and double SH3 domain (FCHSD) proteins, so named as they contain an N-terminal F-BAR domain and two SH3 domains at the C-terminus. Vertebrates harbor two subfamily members, FCHSD1 and FCHSD2, which have been characterized only in silico. Their biological function is still unknown. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  16 HTHTDQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREWSGAPSEEQKDSRNVWAVWRSYLEGVI 95
Cdd:cd07654    1 LRHLEQLSKLQAKHQTECDLLEDIRTYSQKKAAIEREYGQALQKLASQFLKREWPGSGELKPEDDRSGYTVWGAWLEGLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  96 KVSQSRINGCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRKTYQEAEQTAQTVREKADM-EAK 174
Cdd:cd07654   81 AVAQSRQNRCEAYRRYISEPAKTGRSAKEQQLKKCTEQLQRAQAEVQQTVRELSKSRKTYFEREQVAHLAREKAADvQAR 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781 175 YVKT-----------QSVSVTLQSEESKCE--------DY-----------------------HVLDGSFYDHVQSFLIS 212
Cdd:cd07654  161 EARSdlsifqsrtslQKASVKLSARKAECSskataarnDYllnlaatnahqdryyqtdlpaiiKALDGELYDHLKDFLIS 240

                        250       260
                 ....*....|....*....|....
gi 966715781 213 LCQTELETSQSIQDTFQCLLETSS 236
Cdd:cd07654  241 LSHTELETAQVIQETFQRLLETSS 264

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH and double SH3 domains 1 (FCHSD1); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. FCH and double SH3 domains 1 (FCHSD1) contains an N-terminal F-BAR domain and two SH3 domains at the C-terminus. It has been characterized only in silico, and its biological function is still unknown. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  20 DQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREWSGAPSEEQkDSRNVWAVWRSYLEGVIKVSQ 99
Cdd:cd07678    5 EQLSILQTKQQRDAELLEDIRSYSKQRAAIEREYGQALQRLASQFLKRDWHRGGNETE-MDRSVRTVWGAWREGTAATGQ 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781 100 SRINGCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRKTYQEAEQTAQTVREKA-DMEAKYVK- 177
Cdd:cd07678   84 GRVTRLEAYRRLRDEAGKTGRSAKEQVLKKSTEQLQKAQAELLETVKELSKSKKLYGQLERVSEVAKEKAaDVEARLNKs 163

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781 178 -------------------TQSVSVTLQSEESKCE--------------DYHV--------LDGSFYDHVQSFLISLCQT 216
Cdd:cd07678  164 dhgifhskaslqklsakfsAQSAEYSQQLQAARNEyllnlvaanahldhYYQEelpaimkaLDGDLYERLRDPLTSLSHT 243

                        250       260
                 ....*....|....*....|
gi 966715781 217 ELETSQSIQDTFQCLLETSS 236
Cdd:cd07678  244 ELEACEVTQEHFHRIEQATS 263

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. 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 966715781 535 RALYAYEAQTEDELSFPEGAVICILSKHNQEDDGFWEGEFNGAVGVFPAVLVED 588
Cdd:cd11894    3 KALYDYEGQTDDELSFPEGAIIRILNKENQDDDGFWEGEFNGRIGVFPSVLVEE 56

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. 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 966715781 533 LARALYAYEAQTEDELSFPEGAVICILSKHNQE-DDGFWEGEFNGAVGVFPAVLVEDL 589
Cdd:cd11895    1 LARALYSYTGQSPEELSFPEGALIRLLPRAQDGvDDGFWRGEFGGRVGVFPSLLVEEL 58

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Cdc42-Interacting Protein 4 and similar proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. Members of this subfamily typically contain an N-terminal F-BAR domain and a C-terminal SH3 domain. In addition, some members such as FNBP1L contain a central Cdc42-binding HR1 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  20 DQLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKRewsgAPSEEQKDSRNVWAvWRSYLEGVIKVSQ 99
Cdd:cd07653    5 DQFDNLEKHTQKGIDFLERYGKFVKERAAIEQEYAKKLRKLVKKYLPK----KKEEDEYSFSSVKA-FRSILNEVNDIAG 79

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 966715781 100 SRINGCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRKTY----QEAEQtAQTVREKADME 172
Cdd:cd07653   80 QHELIAENLNSNVCKELKTLISELRQERKKHLSEGSKLQQKLESSIKQLEKSKKAYekafKEAEK-AKQKYEKADAD 155

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
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966715781 535 RALYAYEAQTEDELSFPEGAVICIlskHNQEDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11823    3 KALYSYTANREDELSLQPGDIIEV---HEKQDDGWWLGELNGKKGIFPATYVE 52

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 966715781 534 ARALYAYEAQTEDELSFPEGAVICILSKHnqeDDGFWEGEFNGA-VGVFPA 583
Cdd:cd00174    2 ARALYDYEAQDDDELSFKKGDIITVLEKD---DDGWWEGELNGGrEGLFPA 49

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 966715781 533 LARALYAYEAQTEDELSFPEGAVICILSkhnQEDDGFWEGEFNGAVGVFPAVLVED 588
Cdd:cd11877    1 LVRAKFNFEGTNEDELSFDKGDIITVTQ---VVEGGWWEGTLNGKTGWFPSNYVKE 53

The Extended FES-CIP4 Homology (FCH) or F-BAR (FCH and Bin/Amphiphysin/Rvs) domain, a dimerization module that binds and bends membranes; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. F-BAR domain containing proteins, also known as Pombe Cdc15 homology (PCH) family proteins, include Fes and Fer tyrosine kinases, PACSINs/Syndapins, FCHO, PSTPIP, CIP4-like proteins and srGAPs. Many members also contain an SH3 domain and play roles in endocytosis. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules. These tubules have diameters larger than those observed with N-BARs. The F-BAR domains of some members such as NOSTRIN and Rgd1 are important for the subcellular localization of the protein.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781  24 RLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREWSGAPSeeqkdSRNVWAVWRSYLEGvikVSQSRIN 103
Cdd:cd07610    4 LLEKRTELGLDLLKDLREFLKKRAAIEEEYAKNLQKLAKKFSKKPESGKTS-----LGTSWNSLREETES---AATVHEE 75

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 966715781 104 GCENYRSQISDPVKTFRAQKDLQLKKCCEQLARAQADLQVTIRDLEKNRK 153
Cdd:cd07610   76 LSEKLSQLIREPLEKVKEDKEQARKKELAEGEKLKKKLQELWAKLAKKAD 125

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
                   ....*....|....*....|....*....|....*....|....*....|.
gi 966715781   428 VLYGYQASQPDELTIQEQEILELIDDGDmEDWVKARNRAGQVGYVPEKYLQ 478
Cdd:smart00326   7 ALYDYTAQDPDELSFKKGDIITVLEKSD-DGWWKGRLGRGKEGLFPSNYVE 56

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 966715781  536 ALYAYEAQTEDELSFPEGAVICILSKHNqedDGFWEGEFNGAVGVFPAVLVE 587
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESE---DGWWEGINTGRTGLVPANYVE 49

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. 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 966715781 534 ARALYAYEAQTEDELSFPEGAVICILSKHnqeDDGFWEGEFNG-AVGVFPAVLVED 588
Cdd:cd11825    2 VKALYDYRAQRPDELSFCKHAIITNVEKE---DGGWWRGDYGGkKQKWFPANYVEE 54

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 966715781  535 RALYAYEAQTEDELSFPEGAVICILSKhnqEDDGFWEGEFN-GAVGVFPA 583
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEK---SEDGWWKGRNKgGKEGLIPS 47

Fes/CIP4, and EFC/F-BAR homology domain; Alignment extended from. Highly alpha-helical. The cytosolic endocytic adaptor proteins in fungi carry this domain at the N-terminus; several of these have been referred to as muniscin proteins. These N-terminal BAR, N-BAR, and EFC/F-BAR domains are found in proteins that regulate membrane trafficking events by inducing membrane tubulation. The domain dimerizes into a curved structure that binds to liposomes and either senses or induces the curvature of the membrane bilayer to cause biophysical changes to the shape of the bilayer; it also thereby recruits other trafficking factors, such as the GTPase dynamin. Most EFC/F-BAR domain-family members localize to actin-rich structures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966715781   21 QLNRLQLKHQTDLDFLEDLRTYSQKKALIEKDYSQALQKLASQYLKREwsgapSEEQKDSRNVWAVWRSYLEGVIKVSQS 100
Cdd:pfam00611   1 GFKVLLKRLKQGIKLLEELASFLKERAEIEEEYAKKLQKLAKKFLKKK-----KKPEDDGGTLKKAWDELLTETEQLAKQ 75

                  ...
gi 966715781  101 RIN 103
Cdd:pfam00611  76 HLK 78

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 966715781 534 ARALYAYEAQTEDELSFPEGAVICilskhNQE--DDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11961    2 AKALYDYDAAEDNELSFFENDKII-----NIEfvDDDWWLGECHGSRGLFPSNYVE 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966715781 535 RALYAYEAQTEDELSFPEGAVICILSKHnqeDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11772    3 RALYDYEAQHPDELSFEEGDLLYISDKS---DPNWWKATCGGKTGLIPSNYVE 52

Src Homology 3 domain of Cdc42-Interacting Protein 4; This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. It functions downstream of Cdc42 in PDGF-dependent actin reorganization and cell migration, and also regulates the activity of PDGFRbeta. It uses Src as a substrate in regulating the invasiveness of breast tumor cells. CIP4 may also play a role in the pathogenesis of Huntington's disease. Members of this subfamily typically contain an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of CIP4 associates with Gapex-5, a Rab31 GEF. 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 966715781 425 TCSVLYGYQASQPDELTIQEQEILELIDDGDMEDWVKARNRAGQVGYVPEKYLQL 479
Cdd:cd11911    1 TCTALYDFDGTSEGTLSMEEGEILLVLEEDGGDGWTRVRKNNGDEGYVPTSYIEV 55

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, 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 966715781 536 ALYAYEAQTEDELSFPEGAVICILSKhnqEDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11995    5 GMYDYTAQNDDELAFSKGQIINVLNK---EDPDWWKGELNGQVGLFPSNYVK 53

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. 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 966715781 534 ARALYAYEAQTEDELSFPEGAVICIlskHNQEDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11781    2 ARALYPFKAQSAKELSLKKGDIIYI---RRQIDKNWYEGEHNGRVGIFPASYVE 52

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. 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 966715781 428 VLYGYQASQPDELTIQEQEILELIDDGdmEDWVKARNRAGQVGYVPEKYLQ 478
Cdd:cd11764    4 VLYDFTARNSKELSVLKGEYLEVLDDS--RQWWKVRNSRGQVGYVPHNILE 52

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, 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 966715781 534 ARALYAYEAQTEDELSFPEGAVICILSKhnqEDDGFWEGEFNGAVGVFPAVLVEDL 589
Cdd:cd11920    3 ARAVYDFKAQTSKELSFKKGDTVYILRK---IDQNWYEGEHHGRVGIFPISYVEKL 55

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 966715781 534 ARALYAYEAQTEDELSFPEGAVICILSkhnQEDDGFWEGEFN-GAVGVFPAVLVE 587
Cdd:cd11819    2 AKALYDYQAAEDNEISFVEGDIITQIE---QIDEGWWLGVNAkGQKGLFPANYVE 53

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, 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 966715781 536 ALYAYEAQTEDELSFPEGAVICILskhNQEDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11996    5 AMYDYTANNEDELSFSKGQLINVL---NKDDPDWWQGEINGVTGLFPSNYVK 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 966715781 535 RALYAYEAQTEDELSFPEGAvicILSKHNQEDDGFW-EGEFNGAVGVFPAVLVE 587
Cdd:cd11843    3 RALYDYEGQESDELSFKAGD---ILTKLEEEDEQGWcKGRLDGRVGLYPANYVE 53

First Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the first 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 966715781 428 VLYGYQASQPDELTIQEQEILELIDDGDMEDWVKARNRAGQVGYVPEKYLQL 479
Cdd:cd11912    4 VLYDYTASGDDEVSISEGEEVTVLEPDDGSGWTKVRNGSGEEGLVPTSYIEI 55

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. 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 966715781 533 LARALYAYEAQTEDELSFPEGAVICILSKHN--QEDDGFWEGEFNGAVGVFPA 583
Cdd:cd12058    1 LWTALYDYEASGEDELSLRRGDVVEVLSQDAavSGDDGWWAGKIRHRLGIFPA 53

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. 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 966715781 536 ALYAYEAQTEDELSFPEGAVICILSKHnqeDDGFWEGEFNGAVGVFPAVLVEDL 589
Cdd:cd11971    4 AIYDYSKDKDDELSFMEGAIIYVIKKN---DDGWYEGVCNGVTGLFPGNYVESI 54

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, 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 966715781 534 ARALYAYEAQTEDELSFPEGAVICILskhNQEDDGFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11803    3 CRALYDFEPENEGELGFKEGDIITLT---NQIDENWYEGMVNGQSGFFPVNYVE 53

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. 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 966715781 536 ALYAYEAQTEDELSFPEGAVICILSKHNQ--EDDGFWEGEFNGAVGVFPA 583
Cdd:cd12059    4 AVFDYEASAEDELTLRRGDRVEVLSKDSAvsGDEGWWTGKINDRVGIFPS 53

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 966715781 533 LARALYAYEAQTEDELSFPEGAVICILSKHNQEddgFWEGEFNGAVGVFPAVLVE 587
Cdd:cd11805    1 RVQALYDFNPQEPGELEFRRGDIITVLDSSDPD---WWKGELRGRVGIFPANYVQ 52

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 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 966715781 535 RALYAYEAQTEDELSFPEGAVICILSKhnqEDDGFWEGEFNGAVG-VFPAVLVEDL 589
Cdd:cd11969    3 KALYDYRAKRSDELSFCKGALIHNVSK---ETGGWWKGDYGGKVQhYFPSNYVEDV 55

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. 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 966715781 429 LYGYQASQPDELTIQEQEILELIDDGDmEDWVKARNRAGQVGYVPEKYLQ 478
Cdd:cd11768    5 LYDFQPIEPGDLPLEKGEEYVVLDDSN-EHWWRARDKNGNEGYIPSNYVT 53