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 1381325678  24 FSCSIEDPTKQTKFKGIKTYISYRVTPSHTGQPVYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRKRR 103
Cdd:cd07286     1 FQCTIDDPTKQTKFKGMKSYISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1381325678 104 LILWMNHMTSHPVLSQYEGFEHFLMC--GDDKQWKLGKRRAEKDEMV 148
Cdd:cd07286    81 LIWWMDHMCSHPVLARCDAFQHFLTCpsTDEKAWKQGKRKAEKDEMV 127

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. SNX18, like SNX9, 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. 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 1381325678  24 FSCSIEDPTKQTKFKGIKTYISYRVTPSHTGQPVYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRKRR 103
Cdd:cd07286     1 FQCTIDDPTKQTKFKGMKSYISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1381325678 104 LILWMNHMTSHPVLSQYEGFEHFLMC--GDDKQWKLGKRRAEKDEMV 148
Cdd:cd07286    81 LIWWMDHMCSHPVLARCDAFQHFLTCpsTDEKAWKQGKRKAEKDEMV 127

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 1381325678 159 PSEHQDLQDVEERVDSFKSFAKKMDDSVMQLTHGASEMVRKHLGEFRKEFQRMGNAFASLSQAFMLDPPHSSEALNNAIS 238
Cdd:cd07669     1 PTEHQDLQDVEERVDVFKAFSKKMDDSVLQLSNVASELVRKHLGGFRKEFQKLGNAFQAISHSFQLDPPYSSEALNNAIS 80

                  ....*...
gi 1381325678 239 HTGRTYEN 246
Cdd:cd07669    81 HTGRTYEA 88

PhoX homologous domain, present in p47phox and p40phox; Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678   34 QTKFKGIKTYISYRVTPSHTGQP--VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGR---FEEDFIEKRKRRLILWM 108
Cdd:smart00312   5 EKIGDGKHYYYVIEIETKTGLEEwtVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRlnnFSEEFIEKRRRGLEKYL 84

                           90       100
                   ....*....|....*....|
gi 1381325678  109 NHMTSHPVLSQ-YEGFEHFL 127
Cdd:smart00312  85 QSLLNHPELINhSEVVLEFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. SNX18, like SNX9, 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. 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 1381325678  24 FSCSIEDPTKQTKFKGIKTYISYRVTPSHTGQPVYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRKRR 103
Cdd:cd07286     1 FQCTIDDPTKQTKFKGMKSYISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1381325678 104 LILWMNHMTSHPVLSQYEGFEHFLMC--GDDKQWKLGKRRAEKDEMV 148
Cdd:cd07286    81 LIWWMDHMCSHPVLARCDAFQHFLTCpsTDEKAWKQGKRKAEKDEMV 127

WASP-binding domain of Sorting nexin protein; The C-terminal region of the Sorting nexin group of proteins appears to carry a BAR-like (Bin/amphiphysin/Rvs) domain. This domain is very diverse and the similarities with other BAR domains are few. In the Sorting nexins it is associated with family PX, pfam00787.13, and in combination with PX appears to be necessary to bind WASP along with p85 to form a multimeric signalling complex.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678 131 DDKQWKLGKRRAEKDEMVGAHFMLTFQIPSEHQDLQDVEERVDSFKSFAKKMDDSVMQLTHGASEMVRKHLGEFRKEFQR 210
Cdd:pfam10456   1 DEKEWKTGKRKAEKDELVGAMFFLTIEIPEPPLDLQEVEQKVEGFKRFTKKMDDSVKQLLTVGNEFWKKCTGPFKKEYQK 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1381325678 211 MGNAFASLSQAFMLDPPHSSEALNNAISHTGRTYE 245
Cdd:pfam10456  81 IGSAFQLLSQVFEMDGYVGSSALNEAIAHTGKTYE 115

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 1381325678 159 PSEHQDLQDVEERVDSFKSFAKKMDDSVMQLTHGASEMVRKHLGEFRKEFQRMGNAFASLSQAFMLDPPHSSEALNNAIS 238
Cdd:cd07669     1 PTEHQDLQDVEERVDVFKAFSKKMDDSVLQLSNVASELVRKHLGGFRKEFQKLGNAFQAISHSFQLDPPYSSEALNNAIS 80

                  ....*...
gi 1381325678 239 HTGRTYEN 246
Cdd:cd07669    81 HTGRTYEA 88

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 9 and Similar Proteins; 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. This subfamily consists of SNX9, SNX18, SNX33, and similar proteins. 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. 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 1381325678 167 DVEERVDSFKSFAKKMDDSVMQLTHGASEMVRKHLGEFRKEFQRMGNAFASLSQAFMLDPPHSSEALNNAISHTGRTYEN 246
Cdd:cd07626     1 DVEQQVDAFKKFVKSMDDSVKNLINIAQEQAKKHQGPYKKEYQKIGQAFTSLGTAFELDETPTSVPLTQAIKHTGQAYEE 80

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 1381325678  25 SCSIEDPtkQTKFKGIKTYISYRVTPSHTGQP---VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRK 101
Cdd:cd06093     1 SVSIPDY--EKVKDGGKKYVVYIIEVTTQGGEewtVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNLDPEFIEERR 78

                          90       100
                  ....*....|....*....|....*.
gi 1381325678 102 RRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd06093    79 KQLEQYLQSLLNHPELRNSEELKEFL 104

The phosphoinositide binding Phox Homology domain of yeast sorting nexin Vps5p; 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. Vsp5p is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10p, the Golgi-resident membrane protein A-ALP, and endopeptidase Kex2. The PX domain of Vps5p binds phosphatidylinositol-3-phosphate (PI3P). Similar to SNX1, Vps5p contains 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  24 FSCSIEDPTKQTKFkgIKTYISYRV---TPSHTGQP----VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDF 96
Cdd:cd06861     1 FEITVGDPHKVGDL--TSAHTVYTVrtrTTSPNFEVssfsVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDNF 78

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1381325678  97 IEKRKRRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd06861    79 VEQRRAALEKMLRKIANHPVLQKDPDFRLFL 109

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 1381325678  38 KGI-KTYISYRVTPSHTGQPVYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRKRRLILWMNHMTSHPV 116
Cdd:cd06866    12 KGLfLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGSADREFLEARRRGLSRFLNLVARHPV 91

                          90
                  ....*....|.
gi 1381325678 117 LSQYEGFEHFL 127
Cdd:cd06866    92 LSEDELVRTFL 102

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 1381325678  27 SIEDPTKQtkFKGIKTYISYRVTpSHTGQP--------VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQAT----GRFEE 94
Cdd:cd06860     4 TVDNPEKH--VTTLETYITYRVT-TKTTRSefdsseysVRRRYQDFLWLRQKLEESHPTHIIPPLPEKHSVkgllDRFSP 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1381325678  95 DFIEKRKRRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd06860    81 EFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

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 1381325678 164 DLQDVEERVDSFKSFAKKMDDSVMQLTHGASEMVRKHLGEFRKEFQRMGNAFASLSQAFMLDPPHSSEALNNAISHTGRT 243
Cdd:cd07668     6 DLVEIEQKCEAVGRFTKAMDDGVKELLTVGQEHWKRCTGPLPKEYQKIGKALQSLATVFSTSGYQGETDLNDAITEAGKT 85

                  ..
gi 1381325678 244 YE 245
Cdd:cd07668    86 YE 87

The phosphoinositide binding Phox Homology domain of Sorting Nexin 4; 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. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  24 FSCSIEDPTKQTKFKGIK---TYISYRV------TPSHTGQP-----VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQA- 88
Cdd:cd06864     1 MEITVTEAEKRTGGSAMNlkeTYTVYLIetkiveHESEEGLSkklssLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAm 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1381325678  89 -------TGRFEEDFIEKRKRRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd06864    81 fmwqklsSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFL 126

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 1381325678  57 VYRRYKHFDWLYNRLlHKFTVISVPHLPEK---------QATGRFEEDFIEKRKRRLILWMNHMTSHPvLSQYEGFEHFL 127
Cdd:cd06894    40 VRRRYSDFEWLRSEL-ERDSKIVVPPLPGKalkrqlpfrGDDGIFEEEFIEERRKGLETFINKVAGHP-LAQNEKCLHMF 117

                  ..
gi 1381325678 128 MC 129
Cdd:cd06894   118 LQ 119

The phosphoinositide binding Phox Homology domain of Sorting Nexin 10; 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. SNX10 may be involved in the regulation of endosome homeostasis. Its expression induces the formation of giant vacuoles in mammalian cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  28 IEDPTKQTKFKGiKTYISYRVTpSHTGQP--------VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFE-EDFIE 98
Cdd:cd06898     4 VRDPRTHKEDDW-GSYTDYEIF-LHTNSMcftlktscVRRRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRFNnEGFIE 81

                          90       100
                  ....*....|....*....|....*....
gi 1381325678  99 KRKRRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd06898    82 ERQQGLQDFLEKVLQTPLLLSDSRLHLFL 110

The phosphoinositide binding Phox Homology domain of the fungal protein YPT35; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of YPT35 proteins from the fungal subkingdom Dikarya. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction. The PX domain of YPT35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to members of the Yip1p protein family, which localize to the ER and Golgi. YPT35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  38 KGIKTYISYRV---TPSHTGQPV--YRRYKHFDWLYNRLLHKF---TVISVPHLPEK----QATGRFEEDFIEKRKRRLI 105
Cdd:cd07280    17 TGGGAYVVWKItieTKDLIGSSIvaYKRYSEFVQLREALLDEFprhKRNEIPQLPPKvpwyDSRVNLNKAWLEKRRRGLQ 96

                          90       100
                  ....*....|....*....|...
gi 1381325678 106 LWMNHMTSHPVLSQYEGFEHFLM 128
Cdd:cd07280    97 YFLNCVLLNPVFGGSPVVKEFLL 119

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 1381325678  39 GIKTYISYRVTPSHTGQP------VYRRYKHFDWLYNRLLHKFtvisvPHL------PEKQATGRFEEDFIEKRKRRLIL 106
Cdd:cd07279    14 GEKKYVVYQLAVVQTGDPdtqpafIERRYSDFLKLYKALRKQH-----PQLmakvsfPRKVLMGNFSSELIAERSRAFEQ 88

                          90       100
                  ....*....|....*....|.
gi 1381325678 107 WMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd07279    89 FLGHILSIPNLRDSKAFLDFL 109

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. SNX2 is a component 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 efficient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex. Similar to SNX1, SNX2 contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX domain of SNX2 preferentially binds phosphatidylinositol-3-phosphate (PI3P), but not PI(3,4,5)P3. Studies on mice deficient with SNX1 and/or SNX2 suggest that they provide an essential function in embryogenesis and are functionally redundant.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  27 SIEDPTKQTKfkGIKTYISYRVTP-------SHTGQPVYRRYKHFDWLYNRLLHKFTVIS--VPHLPEKQATGRFE---- 93
Cdd:cd07282     4 GVSDPEKVGD--GMNAYMAYRVTTktslsmfSRSEFSVRRRFSDFLGLHSKLASKYLHVGyiVPPAPEKSIVGMTKvkvg 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1381325678  94 -ED-----FIEKRKRRLILWMNHMTSHPVLSQYEGFEHFL 127
Cdd:cd07282    82 kEDsssteFVEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

The phosphoinositide binding Phox Homology domain of Sorting Nexin 13; 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. SNX13, also called RGS-PX1, contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs. It specifically binds to the stimulatory subunit of the heterotrimeric G protein G(alpha)s, serving as its GTPase activating protein, through the RGS domain. It preferentially binds phosphatidylinositol-3-phosphate (PI3P) through the PX domain and is localized in early endosomes. SNX13 is involved in endosomal sorting of EGFR into multivesicular bodies (MVB) for delivery to the lysosome.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1381325678  57 VYRRYKHFDWLYNRLLHKFTVISVPHLPEKQATGRFEEDFIEKRKRRLILWMNHMTSHPVLSQYEGFEHFLM 128
Cdd:cd06873    43 VYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFLEKRRKMLNQYLQSLLNPEVLDANPGLQEIVL 114

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3; 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. SNX3 associates with early endosomes through a PX domain-mediated interaction with phosphatidylinositol-3-phosphate (PI3P). It 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. SNX3 is required for the formation of multivesicular bodies, which function as transport intermediates to late endosomes. It also promotes cell surface expression of the amiloride-sensitive epithelial Na+ channel (ENaC), which is critical in sodium homeostasis and maintenance of extracellular fluid volume.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  57 VYRRYKHFDWLYNRLLHKFTVISVP--------HLPEKQATGRFEEDFIEKRKRRLILWMNHMTSHPvLSQYEGFEHFLM 128
Cdd:cd07293    40 VRRRYSDFEWLRSELERESKVVVPPlpgkalfrQLPFRGDDGIFDDSFIEERKQGLEQFLNKVAGHP-LAQNERCLHMFL 118

The phosphoinositide binding Phox Homology Domain of Cytokine-Independent Survival Kinase; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Cytokine-independent survival kinase (CISK), also called Serum- and Glucocorticoid-induced Kinase 3 (SGK3), plays a role in cell growth and survival. It is expressed in most tissues and is most abundant in the embryo and adult heart and spleen. It was originally discovered in a screen for antiapoptotic genes. It phosphorylates and inhibits the proapoptotic proteins, Bad and FKHRL1. CISK/SGK3 also regulates many transporters, ion channels, and receptors. It plays a critical role in hair follicle morphogenesis and hair cycling. N-terminal to a catalytic kinase domain, CISK contains a PX domain which binds highly phosphorylated PIs, directs membrane localization, and regulates the enzyme's activity.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1381325678  26 CSIEDPTKQTKFKGIKTYISYRVTPSHtgqpVYRRYKHFDWLYNRLLHKFTVISVpHLPEKQATGR-FEEDFIEKRKRRL 104
Cdd:cd06870     9 SSDEDREKKKRFTVYKVVVSVGRSSWF----VFRRYAEFDKLYESLKKQFPASNL-KIPGKRLFGNnFDPDFIKQRRAGL 83

                          90       100
                  ....*....|....*....|....
gi 1381325678 105 ILWMNHMTSHPVLSQYEGFEHFLM 128
Cdd:cd06870    84 DEFIQRLVSDPKLLNHPDVRAFLQ 107

The phosphoinositide binding Phox Homology domain of Sorting Nexin 16; 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. SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1381325678  57 VYRRYKHFDWLYNRLLHKFT--VISVPhlPEKQATGRFEEDFIEKRKRRLILWMNHMTSHPVLSQYEGFEHFLmCGD 131
Cdd:cd07276    37 VFRRYTDFVRLNDKLKQMFPgfRLSLP--PKRWFKDNFDPDFLEERQLGLQAFVNNIMAHKDIAKCKLVREFF-CLD 110