The Bin/Amphiphysin/Rvs (BAR) domain of Amphiphysin I and II; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Amphiphysins function primarily in endocytosis and other membrane remodeling events. They contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin and synaptojanin. They function in synaptic vesicle endocytosis. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. The N-BAR domain of amphiphysin forms a curved dimer with a positively-charged concave face that can drive membrane bending and curvature. Human autoantibodies to amphiphysin-1 hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Mutations in amphiphysin-2 (BIN1) are associated with autosomal recessive centronuclear myopathy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  84 QKLGKADETKDEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASMKLTESLHEVYEPDWYGREDVKMVGEKCDVL 163
Cdd:cd07611    1 QKLGKADETKDEQFEEYVQNFKRQETEGTRLQRELRAYLAAIKGMQEASKKLTESLHEVYEPDWYGRDDVKTIGEKCDLL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791 164 WEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQSSKRKDESRISKAEEEFQKAQKVFEEFNV 243
Cdd:cd07611   81 WEDFHQKLVDGALLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQTSKRKDEGRIAKAEEEFQKAQKVFEEFNV 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 731280791 244 DLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTKLGD 294
Cdd:cd07611  161 DLQEELPSLWSRRVGFYVNTFKNVSSLEAKFHKEISVLCHKLYEVMTKLGE 211

The Bin/Amphiphysin/Rvs (BAR) domain of Amphiphysin I and II; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Amphiphysins function primarily in endocytosis and other membrane remodeling events. They contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin and synaptojanin. They function in synaptic vesicle endocytosis. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. The N-BAR domain of amphiphysin forms a curved dimer with a positively-charged concave face that can drive membrane bending and curvature. Human autoantibodies to amphiphysin-1 hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Mutations in amphiphysin-2 (BIN1) are associated with autosomal recessive centronuclear myopathy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  84 QKLGKADETKDEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASMKLTESLHEVYEPDWYGREDVKMVGEKCDVL 163
Cdd:cd07611    1 QKLGKADETKDEQFEEYVQNFKRQETEGTRLQRELRAYLAAIKGMQEASKKLTESLHEVYEPDWYGRDDVKTIGEKCDLL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791 164 WEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQSSKRKDESRISKAEEEFQKAQKVFEEFNV 243
Cdd:cd07611   81 WEDFHQKLVDGALLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQTSKRKDEGRIAKAEEEFQKAQKVFEEFNV 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 731280791 244 DLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTKLGD 294
Cdd:cd07611  161 DLQEELPSLWSRRVGFYVNTFKNVSSLEAKFHKEISVLCHKLYEVMTKLGE 211

BAR domain; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different protein families. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysin, endophilin, BRAP and Nadrin. BAR domains are also frequently found alongside domains that determine lipid specificity, like pfam00169 and pfam00787 domains in beta centaurins and sorting nexins respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791   70 QWNRVwvggSKQVLQKLGKADETK-DEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASM-------KLTESLHE 141
Cdd:pfam03114   4 QFNRA----SQLLGEKVGGAEKTKlDEDFEELERRFDTTEKEIKKLQKDTKGYLQPNPGARAKQTvleqpeeLLAESMIE 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  142 VYEPDWYGR------EDVKMVGEKCDVLWEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQS 215
Cdd:pfam03114  80 AGKDLGEDSsfgkalEDYGEALKRLAQLLEQLDDRVETNFLDPLRNLLKEFKEIQKHRKKLERKRLDYDAAKTRVKKAKK 159

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 731280791  216 SKRKDESRISKAEEEFQKAQKVFEEFNVDLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTK 291
Cdd:pfam03114 160 KKSSKAKDESQAEEELRKAQAKFEESNEQLKALLPNLLSLEVEFVVNQLVAFVEAQLDFHRQCYQLLEQLQQQLGK 235

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 731280791   671 YKVEALHDFEAANSDELTLQRGDMVLVVpsdseADQDAGWLVGVKESDwlqhrdlaaYKGLFPENFTR 738
Cdd:smart00326   3 PQVRALYDYTAQDPDELSFKKGDIITVL-----EKSDDGWWKGRLGRG---------KEGLFPSNYVE 56

The Bin/Amphiphysin/Rvs (BAR) domain of Amphiphysin I and II; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Amphiphysins function primarily in endocytosis and other membrane remodeling events. They contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin and synaptojanin. They function in synaptic vesicle endocytosis. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. The N-BAR domain of amphiphysin forms a curved dimer with a positively-charged concave face that can drive membrane bending and curvature. Human autoantibodies to amphiphysin-1 hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Mutations in amphiphysin-2 (BIN1) are associated with autosomal recessive centronuclear myopathy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  84 QKLGKADETKDEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASMKLTESLHEVYEPDWYGREDVKMVGEKCDVL 163
Cdd:cd07611    1 QKLGKADETKDEQFEEYVQNFKRQETEGTRLQRELRAYLAAIKGMQEASKKLTESLHEVYEPDWYGRDDVKTIGEKCDLL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791 164 WEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQSSKRKDESRISKAEEEFQKAQKVFEEFNV 243
Cdd:cd07611   81 WEDFHQKLVDGALLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQTSKRKDEGRIAKAEEEFQKAQKVFEEFNV 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 731280791 244 DLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTKLGD 294
Cdd:cd07611  161 DLQEELPSLWSRRVGFYVNTFKNVSSLEAKFHKEISVLCHKLYEVMTKLGE 211

The Bin/Amphiphysin/Rvs (BAR) domain of Bridging integrator 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Bridging integrator 2 (Bin2) is a BAR domain containing protein that is mainly expressed in hematopoietic cells. It is upregulated during granulocyte differentiation and is thought to function primarily in this lineage. The BAR domain of Bin2 is closely related to the BAR domains of amphiphysins, which function primarily in endocytosis and other membrane remodeling events. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. Unlike amphiphysins, Bin2 does not appear to contain a C-terminal SH3 domain. Amphiphysin I proteins, enriched in the brain and nervous system, function in synaptic vesicle endocytosis. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), function in intracellular vessicle trafficking. Bin2 can form a stable complex with Bin1 in cells but cannot replace the function of Bin1, and thus, appears to harbor a nonredundant function. The N-BAR domain of amphiphysin forms a curved dimer with a positively-charged concave face that can drive membrane bending and curvature.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  84 QKLGKADETKDEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASMKLTESLHEVYEPDWYGREDVKMVGEKCDVL 163
Cdd:cd07612    1 QKLGKTVETKDEQFEQCAMNLNMQQSDGNRLYKDLKAYLNAVKVMHESSKRLSQTLQDIYEPDWDGHEDLGAIVEGEDLL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791 164 WEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQSSKRKDESRISKAEEEFQKAQKVFEEFNV 243
Cdd:cd07612   81 WNDYEAKLHDQALRTMESYMAQFPDVKERVAKRGRKLVDYDSARHHLEALQNAKKKDDAKIAKAEEEFNRAQVVFEDINR 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 731280791 244 DLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTKLGD 294
Cdd:cd07612  161 ELREELPILYDSRIGCYVTVFQNISNLRDTFYKEMSKLNHDLYNVMKKLED 211

BAR domain; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different protein families. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysin, endophilin, BRAP and Nadrin. BAR domains are also frequently found alongside domains that determine lipid specificity, like pfam00169 and pfam00787 domains in beta centaurins and sorting nexins respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791   70 QWNRVwvggSKQVLQKLGKADETK-DEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASM-------KLTESLHE 141
Cdd:pfam03114   4 QFNRA----SQLLGEKVGGAEKTKlDEDFEELERRFDTTEKEIKKLQKDTKGYLQPNPGARAKQTvleqpeeLLAESMIE 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  142 VYEPDWYGR------EDVKMVGEKCDVLWEDFHQKLVDGSLLTLDTYLGQFPDIKNRIAKRSRKLVDYDSARHHLEALQS 215
Cdd:pfam03114  80 AGKDLGEDSsfgkalEDYGEALKRLAQLLEQLDDRVETNFLDPLRNLLKEFKEIQKHRKKLERKRLDYDAAKTRVKKAKK 159

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 731280791  216 SKRKDESRISKAEEEFQKAQKVFEEFNVDLQEELPSLWSSRVGFYVNTFKNVSSLEAKFHKEIAVLCHKLYEVMTK 291
Cdd:pfam03114 160 KKSSKAKDESQAEEELRKAQAKFEESNEQLKALLPNLLSLEVEFVVNQLVAFVEAQLDFHRQCYQLLEQLQQQLGK 235

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 731280791 669 FLYKVEALHDFEAANSDELTLQRGDMVLVVPSDSEADQDAGWLVGVKESDwlqhrdlaAYKGLFPENFTRRL 740
Cdd:cd11790    1 VLYKVRATHDYTAEDTDELTFEKGDVILVIPFDDPEEQDEGWLMGVKEST--------GCRGVFPENFTERI 64

Src Homology 3 domain of Bridging integrator 1 (Bin1), also called Amphiphysin-2; Bin1 isoforms are localized in many different tissues and may function in intracellular vesicle trafficking. It plays a role in the organization and maintenance of the T-tubule network in skeletal muscle. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Bin1 contains an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR) and a C-terminal SH3 domain. The SH3 domain of Bin1 forms transient complexes with actin, myosin filaments, and CDK5, to facilitate sarcomere organization and myofiber maturation. It also binds dynamin and prevents its self-assembly. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 731280791 669 FLYKVEALHDFEAANSDELTLQRGDMVLVVPSDSEADQDAGWLVGVKESDWLQHRDLAAYKGLFPENFTRRL 740
Cdd:cd12139    1 FLFKVQAQHDYTATDTDELQLKAGDVVLVIPFQNPEEQDEGWLMGVKESDWNQHKKLEKCRGVFPENFTERV 72

The Bin/Amphiphysin/Rvs (BAR) domain of Saccharomyces cerevisiae Reduced viability upon starvation protein 167 and similar proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of fungal proteins with similarity to Saccharomyces cerevisiae Reduced viability upon starvation protein 167 (Rvs167p) and Schizosaccharomyces pombe Hob1 (homolog of Bin1). S. cerevisiae Rvs167p plays a role in regulation of the actin cytoskeleton, endocytosis, and sporulation. It forms a heterodimer with another BAR domain protein Rvs161p. Rvs161p and Rvs167p share common functions but are not interchangeable. Their BAR domains cannot be replaced with each other and the overexpression of one cannot suppress the mutant phenotypes of the other. Rvs167p also interacts with the GTPase activating protein (GAP) Gyp5p, which is involved in ER to Golgi vesicle trafficking. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791  94 DEQFEEYVQNFKRQEAEGTRLQRELRGYLAAIKGMQEASMKLTESLHEVYEPdwygredvkMVGEKCDVL---------- 163
Cdd:cd07599    1 DEQFEELEKDFKSLEKSLKKLIEQSKAFRDSWRSILTHQIAFAKEFAELYDP---------IVGPKESVGshpapestla 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 731280791 164 ----WEDFHQKLVDGSLLTLDTY-----------LGQFPDIKNRIAKRSRKLVDYDSARHHLEALQSSKR----KDESRI 224
Cdd:cd07599   72 rlsrYVKALEELKKELLEELEFFeervilpakelKKYIKKIRKTIKKRDHKKLDYDKLQNKLNKLLQKKKelslKDEKQL 151

                        170       180
                 ....*....|....*....|....*...
gi 731280791 225 SKAEEEFQKAQKVFEEFNVDLQEELPSL 252
Cdd:cd07599  152 AKLERKLEEAKEEYEALNELLKSELPKL 179

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 731280791   671 YKVEALHDFEAANSDELTLQRGDMVLVVpsdseADQDAGWLVGVKESDwlqhrdlaaYKGLFPENFTR 738
Cdd:smart00326   3 PQVRALYDYTAQDPDELSFKKGDIITVL-----EKSDDGWWKGRLGRG---------KEGLFPSNYVE 56

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVPSDSEadqdaGWLVGVKESDwlqhrdlaaYKGLFPENF 736
Cdd:cd00174    1 YARALYDYEAQDDDELSFKKGDIITVLEKDDD-----GWWEGELNGG---------REGLFPANY 51

Src Homology 3 domain of Mixed Lineage Kinases; MLKs 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. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 731280791 675 ALHDFEAANSDELTLQRGDMVLVVPSDSEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11876    4 ALFDYDARGEDELTLRRGQPVEVLSKDAAVSGDEGWWTG----------KIGDKVGIFPSNY 55

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 675 ALHDFEAANSDELTLQRGDMVLVVPSDSEADQDAGWLVGVkesdwLQHRdlaayKGLFPENFTRR 739
Cdd:cd12059    4 AVFDYEASAEDELTLRRGDRVEVLSKDSAVSGDEGWWTGK-----INDR-----VGIFPSNYVTS 58

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVvpSDSEADqdaGWLVGVKESDWLqhrdlaayKGLFPENFTR 738
Cdd:cd11793    2 VQCVHAYTAQQPDELTLEEGDVVNV--LRKMPD---GWYEGERLRDGE--------RGWFPSSYTE 54

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVvpsDSEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11836    1 KYRALYAFEARNPDEISFQPGDIIQV---DESQVAEPGWLAG----------ELKGKTGWFPANY 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 731280791 671 YKVeaLHDFEAANSDELTLQRGDMVLVVPSDSEADQDaGWLVGVkesDWlqhrdLAAYKGLFPENFTRR 739
Cdd:cd11791    2 LRV--LYPYTPQEEDELELVPGDYIYVSPEELDSSSD-GWVEGT---SW-----LTGCSGLLPENYTEK 59

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. 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. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVPsdseaDQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11964    2 KVRAIYDFEAAEDNELTFKAGDIITILD-----DSDPNWWKG----------ETPQGTGLFPSNF 51

Src Homology 3 domain of fungal BOI-like proteins; This subfamily includes the Saccharomyces cerevisiae proteins BOI1 and BOI2, and similar proteins. They contain an N-terminal SH3 domain, a Sterile alpha motif (SAM), and a Pleckstrin homology (PH) domain at the C-terminus. BOI1 and BOI2 interact with the SH3 domain of Bem1p, a protein involved in bud formation. They promote polarized cell growth and participates in the NoCut signaling pathway, which is involved in the control of cytokinesis. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVVPSDSEADQdaGWLVGvkesdwlqhRDLAAYK-GLFPENF 736
Cdd:cd11886    2 LIVIHDFNARSEDELTLKPGDKIELIEDDEEFGD--GWYLG---------RNLRTGEtGLFPVVF 55

Second 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 second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVpsdsEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11778    1 YVEALYDYEAQGDDEISIRVGDRIAVI----RGDDGSGWTYG----------EINGVKGLFPTSY 51

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing protein A; UBASH3A is also called Cbl-Interacting Protein 4 (CLIP4), T cell Ubiquitin LigAnd (TULA), or T cell receptor Signaling (STS)-2. It is only found in lymphoid cells and exhibits weak phosphatase activity. UBASH3A facilitates T cell-induced apoptosis through interaction with the apoptosis-inducing factor AIF. It is involved in regulating the level of phosphorylation of the zeta-associated protein (ZAP)-70 tyrosine kinase. 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVVPSDSEaDQDAGWLVGVkesdwlQHRdlAAYKGLFPENFTRR 739
Cdd:cd11937    3 LRALFQYKPQNIDELMLSPGDYIFVDPTQQS-EASEGWVIGI------SHR--TGCRGFLPENYTER 60

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVpsdSEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd12142    1 YCRVLFDYNPVAPDELALKKGDVIEVI---SKETEDEGWWEG----------ELNGRRGFFPDNF 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVlvvpSDSEAdQDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11818    1 KARALYDFTGENEDELSFKAGDII----TELES-IDEEWMSG----------ELRGKSGIFPKNF 50

Fifth Src homology 3 domain (or SH3E) 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 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVPSDseadqDAGWLVGvkesdwlqhrDLAAYKGLFPENF 736
Cdd:cd11840    1 QVIALFPYTAQNEDELSFQKGDIINVLSKD-----DPDWWRG----------ELNGQTGLFPSNY 50

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVpsdsEADQDAGWLV 712
Cdd:cd11824    1 KYSVLYDYTAQEDDELSISKGDVVAVI----EKGEDGWWTV 37

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVVPSDSEadqdagwlvgvkesDWLQHRDLAAYKGLFPENF 736
Cdd:cd11812    2 VVALYDYTANRSDELTIHRGDIIRVLYKDND--------------NWWFGSLVNGQQGYFPANY 51

First Src homology 3 domain (or SH3A) 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 first SH3 domain (or SH3A) of ITSN2 is expected to bind many protein partners, similar to ITSN1 which has been shown to bind 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 675 ALHDFEAANSDELTLQRGDMVLVvpsDSEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENFTRR 739
Cdd:cd11988    6 ALYPFEARNHDEMSFNAGDIIQV---DEKTVGEPGWLYG----------SFQGNFGWFPCNYVEK 57

Fourth 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVVpsdseADQDAGWLVGVkesdwLQHRDlaaykGLFPENF 736
Cdd:cd11817    2 AVALYDFTGETEEDLSFQRGDRILVT-----EHLDAEWSRGR-----LNGRE-----GIFPRAF 50

Third (or C-terminal) 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 third 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 731280791 675 ALHDFEAANSDELTLQRGDMVLVVPSdseadQDAGWLVGVKESdwlqhrdlAAYKGLFPENFTRR 739
Cdd:cd11780    4 ALYSYTPQNEDELELREGDIVYVMEK-----CDDGWFVGTSER--------TGLFGTFPGNYVAR 55

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 731280791 671 YKVEalHDFEAANSDELTLQRGDMVLVVpsdsEADQDAGWLVGvkesdwlqhrDLAAYKGLFPENFTRRLE 741
Cdd:cd12053    2 YIVE--YDYDAVHEDELTIRVGEIIRNV----KKLEEEGWLEG----------ELNGRRGMFPDNFVKEIK 56

Src Homology 3 domain of eumetazoan Peroxisomal biogenesis factor 13; PEX13 is a peroxin and is required for protein import into the peroxisomal matrix and membrane. It is an integral membrane protein that is essential for the localization of PEX14 and the import of proteins containing the peroxisome matrix targeting signals, PTS1 and PTS2. Mutations of the PEX13 gene in humans lead to a wide range of peroxisome biogenesis disorders (PBDs), the most severe of which is known as Zellweger syndrome (ZS), a severe multisystem disorder characterized by hypotonia, psychomotor retardation, and neuronal migration defects. PEX13 contains two transmembrane regions 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
                 ....*....|....*....|....*....|....*..
gi 731280791 675 ALHDFEAANSDELTLQRGDMVLVVPSDSEADQdAGWL 711
Cdd:cd11864    4 AEYDFVAESEDELSFRAGDKLRLAPKELQPRV-RGWL 39

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 731280791 673 VEALHDFEAANSDELTLQRGDMVLVVPSDseadqDAGWLVGV--KESDWLQhrdlaayKGLFPENF 736
Cdd:cd11883    2 VVALYDFTPKSKNQLSFKAGDIIYVLNKD-----PSGWWDGViiSSSGKVK-------RGWFPSNY 55

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 731280791 672 KVEALHDFEAANSDELTLQRGDMVLVVP-SDSeadqdagwlvgvkESDWLQHRdLAAYKGLFPENFTR 738
Cdd:cd11842    1 KAVALYDFAGEQPGDLAFQKGDIITILKkSDS-------------QNDWWTGR-IGGREGIFPANYVE 54

Third (or C-terminal) 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 731280791 674 EALHDFEAANSDELTLQRGDMVlvvpsDSEADQDAGWLVGVKESdwlqhrdlAAYKGLFPENFTRRL 740
Cdd:cd11917    8 QALYNYMPRNEDELELREGDVI-----DVMEKCDDGWFVGTSRR--------TKFFGTFPGNYVKRL 61