The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; 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. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 430 NLRITGTITAREHSGTGFHPYTLYTVKYETALSGENS-----SGLQQLAYHTVNRRYREFLNLQTRLEEKPDLRKFIkNV 504
Cdd:cd06893    1 NIRIPKTITAKEYKGTGTHPYTLYTVQYETILDVQSEqnpnaASEQPLATHTVNRRFREFLTLQTRLEENPKFRKIM-NV 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149027864 505 KGPKKLFPDLPFGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLALN 557
Cdd:cd06893   80 KGPPKRLFDLPFGNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLAYG 132

Sorting nexin C terminal; This region is found a the C terminal of proteins belonging to the sorting nexin family. It is found on proteins which also contain pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864  736 WLCTENM---QKFLRLVFGTLVQRWLEVQVANLTCPQRWAQYLRLLRESIWPGGVLPKfPRPGRTQAQKAATEKQALQSL 812
Cdd:pfam08628   1 WLRRRALnalKQVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAE-PPPERTEEEKLRTRKEARKLL 79

                          90       100       110
                  ....*....|....*....|....*....|.
gi 149027864  813 MGLLPDFLVEILGVHKCQLSWSLVLESFQQP 843
Cdd:pfam08628  80 LSLIPDALGSVVGRENAREAARRVFDMLQNP 110

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; 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. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 430 NLRITGTITAREHSGTGFHPYTLYTVKYETALSGENS-----SGLQQLAYHTVNRRYREFLNLQTRLEEKPDLRKFIkNV 504
Cdd:cd06893    1 NIRIPKTITAKEYKGTGTHPYTLYTVQYETILDVQSEqnpnaASEQPLATHTVNRRFREFLTLQTRLEENPKFRKIM-NV 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149027864 505 KGPKKLFPDLPFGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLALN 557
Cdd:cd06893   80 KGPPKRLFDLPFGNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLAYG 132

PXA domain; This domain is associated with PX domains pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864    1 MIIRDFVLSWYRSVSHEKTFEAEMEASMKGLVQELRRRMSIVD-SHALTQRVLTLCGCHLQSYIQAKGATAKEQscPVEP 79
Cdd:pfam02194  14 LIIRDFVQSWYSKISSDPEFPNEVRQTLRHALRELSQRLRKVDlASLLLSRLLPLLTSHLEDYRKAEEAVRGKK--LNEL 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864   80 SQLWDAYCQVTTPHPAMSC--------PTTEVTYARGIVNLILKELVPKPHLETRTGRHVVVELITCNVILPLISKLSDP 151
Cdd:pfam02194  92 DLALASKYLALKPHPALSPvllsssqsREAEQKYLRLLVDGLLPLLLPPEDLESRPVRVLVREILACLVLLPVINKLSDP 171

                         170
                  ....*....|
gi 149027864  152 DWIHLILVSI 161
Cdd:pfam02194 172 DFINELIVKL 181

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 149027864   437 ITAREHSGTGFHPYTLYTVKYETALSgenssglqqlaYHTVNRRYREFLNLQTRLeekpdLRKFiknvkgPKKLFPDLP- 515
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGLE-----------EWTVSRRYSDFLELHSKL-----KKHF------PRSILPPLPg 58

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 149027864   516 ------FGNMDSDRVEARKSLLESFLRQLCAIPEIAN-SEEVQEFL 554
Cdd:smart00312  59 kklfgrLNNFSEEFIEKRRRGLEKYLQSLLNHPELINhSEVVLEFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; 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. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 430 NLRITGTITAREHSGTGFHPYTLYTVKYETALSGENS-----SGLQQLAYHTVNRRYREFLNLQTRLEEKPDLRKFIkNV 504
Cdd:cd06893    1 NIRIPKTITAKEYKGTGTHPYTLYTVQYETILDVQSEqnpnaASEQPLATHTVNRRFREFLTLQTRLEENPKFRKIM-NV 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149027864 505 KGPKKLFPDLPFGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLALN 557
Cdd:cd06893   80 KGPPKRLFDLPFGNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLAYG 132

PXA domain; This domain is associated with PX domains pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864    1 MIIRDFVLSWYRSVSHEKTFEAEMEASMKGLVQELRRRMSIVD-SHALTQRVLTLCGCHLQSYIQAKGATAKEQscPVEP 79
Cdd:pfam02194  14 LIIRDFVQSWYSKISSDPEFPNEVRQTLRHALRELSQRLRKVDlASLLLSRLLPLLTSHLEDYRKAEEAVRGKK--LNEL 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864   80 SQLWDAYCQVTTPHPAMSC--------PTTEVTYARGIVNLILKELVPKPHLETRTGRHVVVELITCNVILPLISKLSDP 151
Cdd:pfam02194  92 DLALASKYLALKPHPALSPvllsssqsREAEQKYLRLLVDGLLPLLLPPEDLESRPVRVLVREILACLVLLPVINKLSDP 171

                         170
                  ....*....|
gi 149027864  152 DWIHLILVSI 161
Cdd:pfam02194 172 DFINELIVKL 181

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 149027864 430 NLRITGTITAREhsgtGFHPYTLYTVKYETalsgenssglQQLAYHTVNRRYREFLNLQTRLEEKpdlrkfiknvkGPKK 509
Cdd:cd06093    1 SVSIPDYEKVKD----GGKKYVVYIIEVTT----------QGGEEWTVYRRYSDFEELHEKLKKK-----------FPGV 55

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 149027864 510 LFPDLP----FGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd06093   56 ILPPLPpkklFGNLDPEFIEERRKQLEQYLQSLLNHPELRNSEELKEFL 104

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864  470 QQLAYHTVNRRYREFLNLQTRLEEKPDLRKFiknvkgpkklfPDLP----FGNMDSDRVEARKSLLESFLRQLCAIPEIA 545
Cdd:pfam00787   4 FSLEEWSVRRRYSDFVELHKKLLRKFPSVII-----------PPLPpkrwLGRYNEEFIEKRRKGLEQYLQRLLQHPELR 72

                  ....*....
gi 149027864  546 NSEEVQEFL 554
Cdd:pfam00787  73 NSEVLLEFL 81

The phosphoinositide binding Phox Homology domain of fungal Sorting Nexins 41 and 42; 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. SNX41 and SNX42 (also called Atg20p) form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 431 LRITGTITAREHSGTgfhPYTLYTVKYEtalsgenssglqqlaYHTVNRRYREFLNLQTRLE------------EKPDLR 498
Cdd:cd06867    2 IQIVDAGKSSEGGSG---SYIVYVIRLG---------------GSEVKRRYSEFESLRKNLTrlyptliippipEKHSLK 63

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 149027864 499 KFIKNVKGPKKlfpdlpfgnmDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd06867   64 DYAKKPSKAKN----------DAKIIERRKRMLQRFLNRCLQHPILRNDIVFQKFL 109

The phosphoinositide binding Phox Homology domain of Sorting Nexin 27; 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. SNX27 contains an N-terminal PDZ domain followed by a PX domain and a Ras-Associated (RA) domain. It binds G protein-gated potassium (Kir3) channels, which play a role in neuronal excitability control, through its PDZ domain. SNX27 downregulates Kir3 channels by promoting their movement in the endosome, reducing surface expression and increasing degradation. SNX27 also associates with 5-hydroxytryptamine type 4 receptor (5-HT4R), cytohesin associated scaffolding protein (CASP), and diacylglycerol kinase zeta, and may play a role in their intracellular trafficking and endocytic recycling. The SNX27 PX domain preferentially binds to phosphatidylinositol-3-phosphate (PI3P) and is important for targeting to the early endosome.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 479 RRYREFLNLQTRLeekpdlrkfiknvkgpKKLFPDLPFGNMDS--------DRVEARKSLLESFLRQLCAIPEIANSEEV 550
Cdd:cd06886   36 RRYREFANLHQNL----------------KKEFPDFQFPKLPGkwpfslseQQLDARRRGLEQYLEKVCSIRVIGESDIM 99

                 ....*
gi 149027864 551 QEFLA 555
Cdd:cd06886  100 QDFLS 104

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 149027864 477 VNRRYREFLNLQTRLeeKPDLRKFIKNVKGPKKLFpdlpFGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLAL 556
Cdd:cd07279   38 IERRYSDFLKLYKAL--RKQHPQLMAKVSFPRKVL----MGNFSSELIAERSRAFEQFLGHILSIPNLRDSKAFLDFLQG 111

                 .
gi 149027864 557 N 557
Cdd:cd07279  112 P 112

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 477 VNRRYREFLNLQTRLEE-KPDLRKFIKnvkgPKKLFPDlpfgNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLA 555
Cdd:cd07276   37 VFRRYTDFVRLNDKLKQmFPGFRLSLP----PKRWFKD----NFDPDFLEERQLGLQAFVNNIMAHKDIAKCKLVREFFC 108

                 ..
gi 149027864 556 LN 557
Cdd:cd07276  109 LD 110

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 433 ITGTITAREHSGTgfhpYTLY--TVKYETALSGENSsglqqlaYHTVnRRYREFLNLQTRLEEK-PDLRKfiknVKGPKK 509
Cdd:cd06873    9 IINTGIVKEHGKT----YAVYaiSVTRIYPNGQEES-------WHVY-RRYSDFHDLHMRLKEKfPNLSK----LSFPGK 72

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 149027864 510 LFpdlpFGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFLA 555
Cdd:cd06873   73 KT----FNNLDRAFLEKRRKMLNQYLQSLLNPEVLDANPGLQEIVL 114

The phosphoinositide binding Phox Homology domain of RPK118-like proteins; 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. Members of this subfamily bear similarity to human RPK118, which contains an N-terminal PX domain, a Microtubule Interacting and Trafficking (MIT) domain, and a kinase domain. RPK118 binds sphingosine kinase, a key enzyme in the synthesis of sphingosine 1-phosphate (SPP), a lipid messenger involved in many cellular events. RPK118 may be involved in transmitting SPP-mediated signaling. It also binds the antioxidant peroxiredoxin-3 (PRDX3) and may be involved in the transport of PRDX3 from the cytoplasm to its site of function in the mitochondria. Members of this subfamily also show similarity to sorting nexin 15 (SNX15), which contains PX and MIT domains but does not contain a kinase domain. 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. SNX15 plays a role in protein trafficking processes in the endocytic pathway and the trans-Golgi network. The PX domain of SNX15 interacts with the PDGF receptor and is responsible for the membrane association of the protein.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 448 HP--YTLYTVKYETaLSGENSSGLQQLayhTVNRRYREFLNLQTrleekpDLRKFIKNVKGPKKLFPDLP----FGNMDS 521
Cdd:cd07287   13 HPkgYTVYKVTARI-VSRKNPEDVQEI---VVWKRYSDFKKLHK------DLWQIHKNLCRQSELFPPFAkakvFGRFDE 82

                         90       100       110
                 ....*....|....*....|....*....|...
gi 149027864 522 DRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd07287   83 SVIEERRQCAEDLLQFSANIPALYNSSQLEDFF 115

The phosphoinositide binding Phox Homology domain of uncharacterized fungal proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized fungal proteins containing a PX domain. PX domain harboring proteins 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. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 470 QQLAYHTVNRRYREFLNLQTRLeekpdLRKFiknvkgPKKLFPDLPFGNMdSDRVEARKSLlESFLRQLCAIPEIANSEE 549
Cdd:cd06869   45 EEYRTIYVARRYSDFKKLHHDL-----KKEF------PGKKLPKLPHKDK-LPREKLRLSL-RQYLRSLLKDPEVAHSSI 111

                 ....*
gi 149027864 550 VQEFL 554
Cdd:cd06869  112 LQEFL 116

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 149027864 449 PYTLYTVKYETalsgenSSGLQQLAYHTVNRRYREFLNLQTRLEEKpdlrkfiknvkGPKKLFPDLP----FGNMDSDRV 524
Cdd:cd06861   17 AHTVYTVRTRT------TSPNFEVSSFSVLRRYRDFRWLYRQLQNN-----------HPGVIVPPPPekqsVGRFDDNFV 79

                         90       100       110
                 ....*....|....*....|....*....|
gi 149027864 525 EARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd06861   80 EQRRAALEKMLRKIANHPVLQKDPDFRLFL 109

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 437 ITAREHSGTGFHPYTLYTVKYETALSgenssgLQQLAYHTVNRRYREFLNLQTRLEEKPDLrkFIKNVKGpKKLFPDLPF 516
Cdd:cd07293    6 VTNPQTVGVGRGRFTTYEIRLKTNLP------IFKLKESTVRRRYSDFEWLRSELERESKV--VVPPLPG-KALFRQLPF 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 149027864 517 ----GNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd07293   77 rgddGIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFL 118

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 441 EHSGTGFHPYTLYTVKYETALSGENSSGLqqlayhTVNRRYREFLNLQTRLEEKPDLRKFI------KNVKGPKKlfpdL 514
Cdd:cd07282    9 EKVGDGMNAYMAYRVTTKTSLSMFSRSEF------SVRRRFSDFLGLHSKLASKYLHVGYIvppapeKSIVGMTK----V 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 149027864 515 PFGNMDSDR---VEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd07282   79 KVGKEDSSStefVEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

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 149027864 436 TITAREHSGTGFHPYTLYTVKYETALSGENSSGLQqlayhtVNRRYREFLNLQTRLEEK-------PDLRKFIknVKGPK 508
Cdd:cd07284    4 TVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFE------VRRRYQDFLWLKGRLEEAhptliipPLPEKFV--MKGMV 75

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 149027864 509 KLFPDlpfgnmdsDRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd07284   76 ERFNE--------DFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113

The phosphoinositide binding Phox Homology domain of Sorting Nexin 20; 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. 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. The PX domain of SNX20 binds PIs and targets the SNX20/PSGL-1 complex to endosomes. SNX20 may function in the sorting and cycling of PSGL-1 into endosomes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 149027864 477 VNRRYREFLNLQTRLEEkpDLRKFIKNVKGPKKLFPdlpfGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQEFL 554
Cdd:cd07300   38 IERRYSDFLKLHQELLS--DFSEELEDVVFPKKKLT----GNFSEEIIAERRVALRDYLTLLYSLRFVRRSQAFQDFL 109

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 149027864 477 VNRRYREFLNLQTRLEEkpdlrkfiknvKGPKKLFPDLP-----FGNMD---SDRVEARKSLLESFLRQLCAIPEIANSE 548
Cdd:cd06860   39 VRRRYQDFLWLRQKLEE-----------SHPTHIIPPLPekhsvKGLLDrfsPEFVATRMRALHKFLNRIVEHPVLSFNE 107

                 ....*.
gi 149027864 549 EVQEFL 554
Cdd:cd06860  108 HLKVFL 113

The phosphoinositide binding Phox Homology domain of Sorting Nexin 22; 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. SNX22 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. The biological function of SNX22 is not yet known.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149027864 440 REHSGTGfHPYTLYTVkyETALSGENssglqqlayHTVNRRYREFLNLQTRleekpdLRKFIKNVKGPKKLFPDLpfgnm 519
Cdd:cd06880   10 LEVDESE-KPYTVFTI--EVLVNGRR---------HTVEKRYSEFHALHKK------LKKSIKTPDFPPKRVRNW----- 66

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 149027864 520 dSDRV-EARKSLLESFLRQLCAIPEIanSEEVQEFLALNT 558
Cdd:cd06880   67 -NPKVlEQRRQGLEAYLQGLLKINEL--PKQLLDFLGVRH 103

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 149027864 476 TVNRRYREFLNLQTRLeekpdLRKFiknvkgPKKLFPDLP----FGNMDSDRVEARKSLLESFLRQLCAIPEIANSEEVQ 551
Cdd:cd06862   33 TVSRRYKHFDWLYERL-----VEKY------SCIAIPPLPekqvTGRFEEDFIEKRRERLELWMNRLARHPVLSQSEVFR 101

                 ...
gi 149027864 552 EFL 554
Cdd:cd06862  102 HFL 104