The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 9; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. 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 1958649608 419 EAPDLDLIEIEQKCDAVGKFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLAAVFSSSGYQGETDLNNAIT 498
Cdd:cd07668     1 EAPDLDLVEIEQKCEAVGRFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLATVFSTSGYQGETDLNDAIT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 499 EAGKTYEEIASLVAEQPKKDLHFLMECNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITPQDKQTMVKRVGTMS 578
Cdd:cd07668    81 EAGKTYEEIASLVAEQPKKDLHFLMETNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITLQDKQNMVKRVSTMS 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958649608 579 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALGRFPVM 628
Cdd:cd07668   161 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALSRFPVM 210

Src Homology 3 domain of Sorting nexin 9; Sorting nexin 9 (SNX9), also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains BAR 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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1958649608  37 EARVMYDFAAEPGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEIL 93
Cdd:cd11898     1 KARVLYDFAAEPGNNELTVKEGEIITVTNPNVGGGWIEAKNSQGERGLVPTDYVEIV 57

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 9; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. 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 1958649608 419 EAPDLDLIEIEQKCDAVGKFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLAAVFSSSGYQGETDLNNAIT 498
Cdd:cd07668     1 EAPDLDLVEIEQKCEAVGRFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLATVFSTSGYQGETDLNDAIT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 499 EAGKTYEEIASLVAEQPKKDLHFLMECNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITPQDKQTMVKRVGTMS 578
Cdd:cd07668    81 EAGKTYEEIASLVAEQPKKDLHFLMETNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITLQDKQNMVKRVSTMS 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958649608 579 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALGRFPVM 628
Cdd:cd07668   161 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALSRFPVM 210

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 283 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGSAIPIPSLPDKQVTGRFEEEFIKMRME 362
Cdd:cd07285     1 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGLAIPIPSLPDKQVTGRFEEEFIKMRME 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958649608 363 RLQAWMTRMCRHPVVSESEVFQQFLNFRDEKEWKTGKRKAEKDELV 408
Cdd:cd07285    81 RLQAWMTRMCRHPVISESEVFQQFLNFRDEKEWKTGKRKAEKDETV 126

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 308 TPTNTNRSVNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:pfam00787   3 TFSLEEWSVRRRYSDFVELHKKLLRKFPSVI-IPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFL 81

                  ...
gi 1958649608 388 NFR 390
Cdd:pfam00787  82 ESD 84

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 1958649608   35 SQEARVMYDFAAEpGNNELTVNEGEIITITNpNVGGGWLEGKNSKGEQGLVPTDYVE 91
Cdd:smart00326   2 GPQVRALYDYTAQ-DPDELSFKKGDIITVLE-KSDDGWWKGRLGRGKEGLFPSNYVE 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 1958649608  39 RVMYDFAAEPGNnELTVNEGEIITITNpNVGGGWLEGKNSKGEQGLVPT 87
Cdd:pfam00018   1 VALYDYTAQEPD-ELSFKKGDIIIVLE-KSEDGWWKGRNKGGKEGLIPS 47

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 9; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. 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 1958649608 419 EAPDLDLIEIEQKCDAVGKFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLAAVFSSSGYQGETDLNNAIT 498
Cdd:cd07668     1 EAPDLDLVEIEQKCEAVGRFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLATVFSTSGYQGETDLNDAIT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 499 EAGKTYEEIASLVAEQPKKDLHFLMECNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITPQDKQTMVKRVGTMS 578
Cdd:cd07668    81 EAGKTYEEIASLVAEQPKKDLHFLMETNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITLQDKQNMVKRVSTMS 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958649608 579 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALGRFPVM 628
Cdd:cd07668   161 YALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALSRFPVM 210

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 283 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGSAIPIPSLPDKQVTGRFEEEFIKMRME 362
Cdd:cd07285     1 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGLAIPIPSLPDKQVTGRFEEEFIKMRME 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958649608 363 RLQAWMTRMCRHPVVSESEVFQQFLNFRDEKEWKTGKRKAEKDELV 408
Cdd:cd07285    81 RLQAWMTRMCRHPVISESEVFQQFLNFRDEKEWKTGKRKAEKDETV 126

The phosphoinositide binding Phox Homology domain of Sorting Nexins 9 and 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX9, SNX18, and similar proteins. They contain an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 283 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFgSAIPIPSLPDKQVTGRFEEEFIKMRME 362
Cdd:cd06862     1 YHCTVTNPKKESKFKGLKSFIAYQITPTHTNVTVSRRYKHFDWLYERLVEKY-SCIAIPPLPEKQVTGRFEEDFIEKRRE 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958649608 363 RLQAWMTRMCRHPVVSESEVFQQFLNFRDEKEWKTGKRKAEKDELV 408
Cdd:cd06862    80 RLELWMNRLARHPVLSQSEVFRHFLTCTDEKDWKSGKRKAEKDELV 125

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 33; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). 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 1958649608 424 DLIEIEQKCDAVGKFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLAAVFSSSGYQGETDLNNAITEAGKT 503
Cdd:cd07669     6 DLQDVEERVDVFKAFSKKMDDSVLQLSNVASELVRKHLGGFRKEFQKLGNAFQAISHSFQLDPPYSSEALNNAISHTGRT 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 504 YEEIASLVAEQPKKDLHFLMECNHEYKGFLGCFPDIIGAHKGAIEKVKESDKLVATSKITPQDKQTMVKRVGTMSYALQA 583
Cdd:cd07669    86 YEAVGEMFAEQPKNDLFQMLDTLSLYQGLLSNFPDIIHLQKGAFAKVKESQRMSDEGRMDQDEADGIRKRCRVVGFALQA 165

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 1958649608 584 EMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQAL 622
Cdd:cd07669   166 EMNHFHQRRELDFKQMMQHYLRQQIIFYQRVSQQLEKTL 204

Src Homology 3 domain of Sorting nexin 9; Sorting nexin 9 (SNX9), also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains BAR 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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1958649608  37 EARVMYDFAAEPGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEIL 93
Cdd:cd11898     1 KARVLYDFAAEPGNNELTVKEGEIITVTNPNVGGGWIEAKNSQGERGLVPTDYVEIV 57

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 308 TPTNTNRSVNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:pfam00787   3 TFSLEEWSVRRRYSDFVELHKKLLRKFPSVI-IPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFL 81

                  ...
gi 1958649608 388 NFR 390
Cdd:pfam00787  82 ESD 84

The Phox Homology domain, a phosphoinositide binding module; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to membranes. Proteins containing PX domains interact with PIs and have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. Many members of this superfamily bind phosphatidylinositol-3-phosphate (PI3P) but in some cases, other PIs such as PI4P or PI(3,4)P2, among others, are the preferred substrates. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction, as in the cases of p40phox, p47phox, and some sorting nexins (SNXs). The PX domain is conserved from yeast to humans and is found in more than 100 proteins. The majority of PX domain-containing proteins are SNXs, which play important roles in endosomal sorting.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 298 GLKSYIEYQLTPTNTN---RSVNHRYKHFDWLYERLLVKFGSaIPIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRH 374
Cdd:cd06093    13 GGKKYVVYIIEVTTQGgeeWTVYRRYSDFEELHEKLKKKFPG-VILPPLPPKKLFGNLDPEFIEERRKQLEQYLQSLLNH 91

                          90
                  ....*....|...
gi 1958649608 375 PVVSESEVFQQFL 387
Cdd:cd06093    92 PELRNSEELKEFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexins 1 and 2; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX1, SNX2, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1. SNX1 and SNX2 are components of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi. The retromer consists of a cargo-recognition subcomplex and a subcomplex formed by a dimer of sorting nexins (SNX1 and/or SNX2), which ensures effcient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 283 FDCVVADPRK-GSkmyGLKSYIEYQL-TPTNT------NRSVNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQVTGRFEE 354
Cdd:cd06859     1 FEISVTDPVKvGD---GMSAYVVYRVtTKTNLpdfkksEFSVLRRYSDFLWLYERLVEKYPGRI-VPPPPEKQAVGRFKV 76

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1958649608 355 --EFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:cd06859    77 kfEFIEKRRAALERFLRRIAAHPVLRKDPDFRLFL 111

The phosphoinositide binding Phox Homology domain of Sorting Nexins 7 and 30; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. This subfamily consists of SNX7, SNX30, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-6, SNX8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of the sorting nexins in this subfamily has yet to be elucidated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 287 VADPRKGSKmyGLKSYIEYQLTpTNTNR--------SVNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQVT----GRFEE 354
Cdd:cd06860     5 VDNPEKHVT--TLETYITYRVT-TKTTRsefdsseySVRRRYQDFLWLRQKLEESHPTHI-IPPLPEKHSVkgllDRFSP 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958649608 355 EFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:cd06860    81 EFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

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 1958649608  38 ARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEI 92
Cdd:cd11912     2 AKVLYDYTAS-GDDEVSISEGEEVTVLEPDDGSGWTKVRNGSGEEGLVPTSYIEI 55

The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 302 YIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFgsaiP---IPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVVS 378
Cdd:cd06866    18 HVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRY----PyrmVPALPPKRIGGSADREFLEARRRGLSRFLNLVARHPVLS 93

                          90
                  ....*....|..
gi 1958649608 379 ESEVFQQFLNFR 390
Cdd:cd06866    94 EDELVRTFLTEP 105

Src Homology 3 domain of Sorting nexin 18; SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. It binds FIP5 and is required for apical lumen formation. It may also play a role in axonal elongation. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX18 also contains BAR 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958649608  38 ARVMYDFAAE-PGnnELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEI 92
Cdd:cd11897     2 ARALYDFRSEnPG--EISLREHEVLSLCSEQDIEGWLEGVNSRGDRGLFPASYVEV 55

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 1958649608  38 ARVMYDFAAEpGNNELTVNEGEIITITNpNVGGGWLEGKNSKGEQGLVPTDY 89
Cdd:cd00174     2 ARALYDYEAQ-DDDELSFKKGDIITVLE-KDDDGWWEGELNGGREGLFPANY 51

The phosphoinositide binding Phox Homology domain of SNX-like proteins; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. This subfamily is composed of uncharacterized proteins, predominantly from plants, with similarity to sorting nexins. A few members show a similar domain architecture as a subfamily of sorting nexins, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX-BAR structural unit is known to determine specific membrane localization.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 286 VVADPRK----GSKMYGLKSYIEYQLT-----PTNTNR--SVNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQV---TGR 351
Cdd:cd06865     3 TVSDPKKeqepSRVPLGGPPYISYKVTtrtniPSYTHGefTVRRRFRDVVALADRLAEAYRGAF-VPPRPDKSVvesQVM 81

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1958649608 352 FEEEFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:cd06865    82 QSAEFIEQRRVALEKYLNRLAAHPVIGLSDELRVFL 117

The phosphoinositide binding Phox Homology domain of Sorting Nexin 7; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX7 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-6, SNX8, SNX30, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX7 has yet to be elucidated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 287 VADPRkgSKMYGLKSYIEYQLTpTNTNRS--------VNHRYKHFDWLYERLLVKFGSAIpIPSLPDKQVTG----RFEE 354
Cdd:cd07284     5 VDEPE--SHVTAIETFITYRVM-TKTSRSefdssefeVRRRYQDFLWLKGRLEEAHPTLI-IPPLPEKFVMKgmveRFNE 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958649608 355 EFIKMRMERLQAWMTRMCRHPVVSESEVFQQFL 387
Cdd:cd07284    81 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113

Src Homology 3 domain of Sorting Nexin 33; SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX33 also contains BAR 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958649608  37 EARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEI 92
Cdd:cd11896     1 KARALYSFQSE-NKEEINIQENEELVIFSENSLDGWLQGQNSRGETGLFPASYVEI 55

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 1958649608  38 ARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEI 92
Cdd:cd11911     2 CTALYDFDGT-SEGTLSMEEGEILLVLEEDGGDGWTRVRKNNGDEGYVPTSYIEV 55

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. 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 1958649608  38 ARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVE 91
Cdd:cd11858     2 YKALYDFAGS-VANELSLKKDDIVYIVQKEDNGWWLAKKLDESKEGWVPAAYLE 54

Third Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. The third SH3 domain of Sla1p can bind ubiquitin while retaining the ability to bind proline-rich ligands; monoubiquitination of target proteins signals internalization and sorting through the endocytic pathway. 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 1958649608  37 EARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKN-SKGEQGLVPTDYVEI 92
Cdd:cd11775     2 RGKVLYDFDAQ-SDDELTVKEGDVVYILDDKKSKDWWMVENvSTGKEGVVPASYIEI 57

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. 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
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1958649608  38 ARVMYDFAAEpGNNELTVNEGEIITITNPNVGGGWLEGKNSkGEQGLVPTDYVEI 92
Cdd:cd11882     2 ARALYACKAE-DESELSFEPGQIITNVQPSDEPGWLEGTLN-GRTGLIPENYVEF 54

Src Homology 3 domain of Formin Binding Protein 1-Like; FormiN Binding Protein 1-Like (FNBP1L), also known as Toca-1 (Transducer of Cdc42-dependent actin assembly), forms a complex with neural Wiskott-Aldrich syndrome protein (N-WASP). The FNBP1L/N-WASP complex induces the formation of filopodia and endocytic vesicles. FNBP1L is required for Cdc42-induced actin assembly and is essential for autophagy of intracellular pathogens. It contains an N-terminal F-BAR domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of the related protein, 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 1958649608  39 RVMYDFaaePGNNE--LTVNEGEIITITNPNVGGGWLEGKNSKGEQGLVPTDYVEI 92
Cdd:cd12072     4 KALYPF---DGSNEgtLAMKEGEVLYIIEEDKGDGWTRARKQNGEEGYVPTSYIEI 56

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. 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 1958649608  39 RVMYDFAAEPgNNELTVNEGEIITITNPNVGGGWLeGKNSKGEQGLVPTDYVEI 92
Cdd:cd11770     3 EALSDFQAEQ-EGDLSFKKGEVLRIISKRADGWWL-AENSKGNRGLVPKTYLKV 54

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3 and related proteins; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily is composed of SNX3, SNX12, and fungal Grd19. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. SNX3/Grp19 associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 315 SVNHRYKHFDWLYERLLVKfgSAIPIPSLPDKQV---------TGRFEEEFIKMRMERLQAWMTRMCRHPVVSESEVFQQ 385
Cdd:cd06894    39 SVRRRYSDFEWLRSELERD--SKIVVPPLPGKALkrqlpfrgdDGIFEEEFIEERRKGLETFINKVAGHPLAQNEKCLHM 116

                  ..
gi 1958649608 386 FL 387
Cdd:cd06894   117 FL 118

The phosphoinositide binding Phox Homology domain of Sorting Nexins 20 and 21; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX20, SNX21, and similar proteins. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. It may function in the sorting and cycling of PSGL-1 into endosomes. SNX21, also called SNX-L, is distinctly and highly-expressed in fetal liver and may be involved in protein sorting and degradation during embryonic liver development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958649608 298 GLKSYIEYQLT-----PTNTNRS-VNHRYKHFDWLYERLLVKFGSAIPIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRM 371
Cdd:cd07279    14 GEKKYVVYQLAvvqtgDPDTQPAfIERRYSDFLKLYKALRKQHPQLMAKVSFPRKVLMGNFSSELIAERSRAFEQFLGHI 93

                          90
                  ....*....|....*.
gi 1958649608 372 CRHPVVSESEVFQQFL 387
Cdd:cd07279    94 LSIPNLRDSKAFLDFL 109