RUN domain found in sorting nexin-29 (SNX29) and similar proteins; SNX29, also called RUN domain-containing protein 2A (RUNDC2A), belongs to the sorting nexin family. Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain, a phospholipid-binding motif, or through protein-protein interactions with membrane-associated protein complexes. Some sorting nexin family members have been shown to facilitate protein sorting. This model contains the RUN domain of SNX29.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  26 RLLDAVKQCQIRFGGRKEIASDSDSRVTCLCAQFEAVLQHGLKRSRGLALTAAAIKQA---AGFASKTETEPVFWYYVKE 102
Cdd:cd17689     1 RLLDAVKQCQIRFGGKTELATESDSRVSCLCAQLEAVLQHGLKTSRSPNLVSSAVTQVsglAGSLGSAETEPTFWPFVKE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 103 VLNKHELQRFYSLRHIASDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSIL 182
Cdd:cd17689    81 HLTKHELERFELLKNIWTDIGRGRAWLRSALNEHSLERYLHILLSNENLLRQYYEDWAFLRDEERSSMLPNMAAGLGSIL 160

                  ....*.
gi 1034596582 183 FAINID 188
Cdd:cd17689   161 FALSID 166

leucine zipper found in the TSC22 domain leucine zipper transcription factors, c-Myc-binding protein, and similar proteins; The family includes TGF-beta-stimulated clone-22 domain (TSC22D) leucine zipper transcription factors, TSC22D1-4, as well as c-Myc-binding protein (MycBP). TSC22D proteins have diverse physiological functions, including cell growth, development, homeostasis, and immune regulation. MycBP, also called associate of Myc 1 (AMY-1), is a novel c-Myc binding protein that may control the transcriptional activity of Myc. It stimulates the activation of E box-dependent transcription by Myc. Members of this family contain a conserved leucine zipper (ZIP) domain. Its first helix is not basic and does not contain the consensus sequence, NXX(A)(A)XX(C/S)R, found in most basic region/leucine zipper (bZIP) proteins. In the bZIP family of transcription factors, the leucine zipper acts as a dimerization domain and the upstream basic region as a DNA-binding domain. However, DNA-binding capability of TSC22D family proteins is not obvious, due to the lack of the basic region found in the original bZIP DNA-binding domains. Similar to bZIP, ZIP forms homo- and heterodimers, resulting in many dimers that may have different effects on transcription.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1034596582 514 ALRQEVDTLKRKVAEQEERqgmkVQALARENEVLK 548
Cdd:cd21936    12 AVREEVDVLKEQIAELEER----ISQLERENSLLR 42

RUN domain found in sorting nexin-29 (SNX29) and similar proteins; SNX29, also called RUN domain-containing protein 2A (RUNDC2A), belongs to the sorting nexin family. Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain, a phospholipid-binding motif, or through protein-protein interactions with membrane-associated protein complexes. Some sorting nexin family members have been shown to facilitate protein sorting. This model contains the RUN domain of SNX29.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  26 RLLDAVKQCQIRFGGRKEIASDSDSRVTCLCAQFEAVLQHGLKRSRGLALTAAAIKQA---AGFASKTETEPVFWYYVKE 102
Cdd:cd17689     1 RLLDAVKQCQIRFGGKTELATESDSRVSCLCAQLEAVLQHGLKTSRSPNLVSSAVTQVsglAGSLGSAETEPTFWPFVKE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 103 VLNKHELQRFYSLRHIASDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSIL 182
Cdd:cd17689    81 HLTKHELERFELLKNIWTDIGRGRAWLRSALNEHSLERYLHILLSNENLLRQYYEDWAFLRDEERSSMLPNMAAGLGSIL 160

                  ....*.
gi 1034596582 183 FAINID 188
Cdd:cd17689   161 FALSID 166

RUN domain; This domain is present in several proteins that are linked to the functions of GTPases in the Rap and Rab families. They could hence play important roles in multiple Ras-like GTPase signalling pathways. The domain is comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  54 CLCAQFEAVLQHGLKRSRGLALTAAAIKQaagfasktetEPVFWYYVKEV-----LNKHELQRFYSLRHI---ASDVGRG 125
Cdd:pfam02759   1 QLCAALEALLSHGLKRSSLLILRAAGLLP----------ERSFWALLERVgklvpPAEELLSSVQELEQIhtpYSPDGRG 70

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1034596582 126 RAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSILFAINIDN 189
Cdd:pfam02759  71 RAWIRLALNEKLLDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1034596582 698 EWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAKFVEERRKQLQNYLRSVMNkviqmVPEFAASP 770
Cdd:pfam00787   8 EWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQ-----HPELRNSE 75

Phox homology (PX) domain protein [Intracellular trafficking and secretion / General function prediction only];

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1034596582 703 RRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNK-----DAKFVEERRKQLQNYLRSVM 756
Cdd:COG5391   177 RRYSDFESLHSILIKLLPLCAIPPLPSKKSNSEYygdrfSDEFIEERRQSLQNFLRRVS 235

RUN domain found in sorting nexin-29 (SNX29) and similar proteins; SNX29, also called RUN domain-containing protein 2A (RUNDC2A), belongs to the sorting nexin family. Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain, a phospholipid-binding motif, or through protein-protein interactions with membrane-associated protein complexes. Some sorting nexin family members have been shown to facilitate protein sorting. This model contains the RUN domain of SNX29.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  26 RLLDAVKQCQIRFGGRKEIASDSDSRVTCLCAQFEAVLQHGLKRSRGLALTAAAIKQA---AGFASKTETEPVFWYYVKE 102
Cdd:cd17689     1 RLLDAVKQCQIRFGGKTELATESDSRVSCLCAQLEAVLQHGLKTSRSPNLVSSAVTQVsglAGSLGSAETEPTFWPFVKE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 103 VLNKHELQRFYSLRHIASDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSIL 182
Cdd:cd17689    81 HLTKHELERFELLKNIWTDIGRGRAWLRSALNEHSLERYLHILLSNENLLRQYYEDWAFLRDEERSSMLPNMAAGLGSIL 160

                  ....*.
gi 1034596582 183 FAINID 188
Cdd:cd17689   161 FALSID 166

RUN domain; This domain is present in several proteins that are linked to the functions of GTPases in the Rap and Rab families. They could hence play important roles in multiple Ras-like GTPase signalling pathways. The domain is comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  54 CLCAQFEAVLQHGLKRSRGLALTAAAIKQaagfasktetEPVFWYYVKEV-----LNKHELQRFYSLRHI---ASDVGRG 125
Cdd:pfam02759   1 QLCAALEALLSHGLKRSSLLILRAAGLLP----------ERSFWALLERVgklvpPAEELLSSVQELEQIhtpYSPDGRG 70

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1034596582 126 RAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSILFAINIDN 189
Cdd:pfam02759  71 RAWIRLALNEKLLDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

The phosphoinositide binding Phox Homology domain of KIF16B kinesin or Sorting Nexin 23; 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. KIF16B, also called sorting nexin 23 (SNX23), is a family-3 kinesin which harbors an N-terminal kinesin motor domain containing ATP and microtubule binding sites, a ForkHead Associated (FHA) domain, and a C-terminal PX domain. The PX domain of KIF16B binds to phosphatidylinositol-3-phosphate (PI3P) in early endosomes and plays a role in the transport of early endosomes to the plus end of microtubules. By regulating early endosome plus end motility, KIF16B modulates the balance between recycling and degradation of receptors. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 668 INVWIPSVFLRGKAANAFHVYQVYIRIKDDEWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAKFVEERRKQ 747
Cdd:cd06874     1 IKITIPRYVLRGQGKDEHFEFEVKITVLDETWTVFRRYSRFRELHKTMKLKYPEVAALEFPPKKLFGNKSERVAKERRRQ 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1034596582 748 LQNYLRSVMNKVIQ-----MVPEFAASPKKETLIQLMPFF 782
Cdd:cd06874    81 LETYLRNFFSVCLKlpacpLYPKVGRTLSKATLCDFSPFF 120

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 1034596582 669 NVWIPSVFLRGKAANAFHVYQVYIRIKD-DEWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAKFVEERRKQ 747
Cdd:cd06093     1 SVSIPDYEKVKDGGKKYVVYIIEVTTQGgEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNLDPEFIEERRKQ 80

                          90
                  ....*....|
gi 1034596582 748 LQNYLRSVMN 757
Cdd:cd06093    81 LEQYLQSLLN 90

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1034596582  125 GRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSMLPTMAAGLNSILFAINID 188
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEELLSKYYEPWAFLRDPEEGEQLLGLLVGLSALDFNLPVD 64

The phosphoinositide binding Phox Homology domain of the Imidazoline Receptor Antisera-Selected; The PX domain is a phosphoinositide binding (PI) module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Imidazoline Receptor Antisera-Selected (IRAS), also called nischarin, contains an N-terminal PX domain, leucine rich repeats, and a predicted coiled coil domain. The PX domain of IRAS binds to phosphatidylinositol-3-phosphate in membranes. Together with the coiled coil domain, it is essential for the localization of IRAS to endosomes. IRAS has been shown to interact with integrin and inhibit cell migration. Its interaction with alpha5 integrin causes a redistribution of the receptor from the cell surface to endosomal structures, suggesting that IRAS may function as a sorting nexin (SNX) which regulates the endosomal trafficking of integrin. 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. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 685 FHVYQVYIRIKDDEWNIYRRYTEFRSLHHKLQNKYpQVRAYNFPPKKAIGNKDAKFVEERRKQLQNYLRSVMNKVIQMVP 764
Cdd:cd06875    17 YTVYIIEVKVGSVEWTVKHRYSDFAELHDKLVAEH-KVDKDLLPPKKLIGNKSPSFVEKRRKELEIYLQTLLSFFQKTMP 95

                  .
gi 1034596582 765 E 765
Cdd:cd06875    96 R 96

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 1034596582 684 AFHVYQVYIRIKDDEWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAKFVEERRKQLQNYLRSVMNKViqmv 763
Cdd:cd06873    26 AISVTRIYPNGQEESWHVYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFLEKRRKMLNQYLQSLLNPE---- 101

                          90
                  ....*....|...
gi 1034596582 764 pEFAASPKKETLI 776
Cdd:cd06873   102 -VLDANPGLQEIV 113

RUN domain found in RUN domain-containing protein 3 (RUNDC3) and similar proteins; RUNDC3 contains two isoforms, RUNDC3A and RUNDC3B. RUNDC3A, also called Rap2-interacting protein 8 (RPIP8), may act as an effector of Rap2A GTPase in neuronal cells. RUNDC3B, also called Rap2-binding protein 9, or Rap2-interacting protein 9 (RPIP-9), contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the Mitogen-Activated Protein Kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. It also contains characteristic binding sites for MAPK intermediates. Both RUNDC3A and RUNDC3B contain a RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  43 EIASDSDSRVTCLCAQFEAVLQHGLKrsrglaltaaAIKQAAGfaskTETEPVFWYYVKEVLNK---HELQRFYSLRHIA 119
Cdd:cd17684    20 ETIDDSSEELINFAAILEQILSHRLK----------PVKPWYG----SEEPRTFWDYIRVACKKvpqNCIASIEQMENIK 85

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1034596582 120 SDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEErSSMLPTMAAGLNSILF 183
Cdd:cd17684    86 SPKAKGRAWIRVALMEKRLSEYLSTALKQTRLTRNFYQDGAIMLSED-ATVLCGMLIGLNAIDF 148

The phosphoinositide binding Phox Homology domain of Modulator of Na,K-ATPase; 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. MONaKA (Modulator of Na,K-ATPase) binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission. MONaKA contains an N-terminal PX domain and a C-terminal catalytic kinase domain. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1034596582 695 KDDEWNIYRRYTEFRSLHHKLQnkyPQVRAYNFPPKKAIGNKDAKFVEERRKQLQNYLRSVM 756
Cdd:cd06871    34 PENSWQVIRRYNDFDLLNASLQ---ISGISLPLPPKKLIGNMDREFIAERQQGLQNYLNVIL 92

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 1034596582 685 FHVYQVYIRIKDDEWN----IYRRYTEFRSLHHKLQNKYPQ-VRAYNFPPKKAIGNKDAKFVEERRKQLQNYLRsvmnkV 759
Cdd:cd07279    18 YVVYQLAVVQTGDPDTqpafIERRYSDFLKLYKALRKQHPQlMAKVSFPRKVLMGNFSSELIAERSRAFEQFLG-----H 92

                          90
                  ....*....|.
gi 1034596582 760 IQMVPEFAASP 770
Cdd:cd07279    93 ILSIPNLRDSK 103

RUN domain found in RUN domain-containing protein 3B (RUNDC3B) and similar proteins; RUN domain-containing protein 3B (RUNDC3B), also called Rap2-binding protein 9, or Rap2-interacting protein 9 (RPIP-9), contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the Mitogen-Activated Protein Kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. It also contains characteristic binding sites for MAPK intermediates. RUNDC3B contains a RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  43 EIASDSDSRVTCLCAQFEAVLQHGLKrsrglaltaaaiKQAAGFAskTETEPVFWYYVKEVLNK--HE-LQRFYSLRHIA 119
Cdd:cd17700    20 ETIDDSSPEFVNFAAILEQILSHRLK------------GQVTWFG--YESPRSFWDYIRVACSKvpHNcICSIENMENVS 85

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1034596582 120 SDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEErSSMLPTMAAGLNSILFA 184
Cdd:cd17700    86 SSRAKGRAWIRVALMEKRLSEYISTALRDFKTTRRFYEDGAIVLGEE-ANMLAGMLLGLNAIDFS 149

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 1034596582 679 GKAANAFHVYQVYIR-----IKDDEWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAK--FVEERRKQLQNY 751
Cdd:cd06859    12 GDGMSAYVVYRVTTKtnlpdFKKSEFSVLRRYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKVKfeFIEKRRAALERF 91

                  ....*.
gi 1034596582 752 LRSVMN 757
Cdd:cd06859    92 LRRIAA 97

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 1034596582 685 FHVYQVYIRIKDDEWNI---------YRRYTEFRSLHHKLQNKYPQVRAYNFPPKKA--------IGNKDAKFVEERRKQ 747
Cdd:cd06864    23 YTVYLIETKIVEHESEEglskklsslWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAmfmwqklsSDTFDPDFVERRRAG 102

                  ....*...
gi 1034596582 748 LQNYLRSV 755
Cdd:cd06864   103 LENFLLRV 110

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 685 FHVYQVYIRIKDDEWNIYRRYTEFRSLHHKLQNKYPQVrAYNFPPKKAIGNK-DAKFVEERRKQLQNYLRSVM--NKVIQ 761
Cdd:cd06870    20 FTVYKVVVSVGRSSWFVFRRYAEFDKLYESLKKQFPAS-NLKIPGKRLFGNNfDPDFIKQRRAGLDEFIQRLVsdPKLLN 98

                  ....*..
gi 1034596582 762 MvPEFAA 768
Cdd:cd06870    99 H-PDVRA 104

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 1034596582 679 GKAANAFHVYQVYIR-----IKDDEWNIYRRYTEFRSLHHKLQNKYPQVrAYNFPP----------KKAIGNKDA---KF 740
Cdd:cd07282    12 GDGMNAYMAYRVTTKtslsmFSRSEFSVRRRFSDFLGLHSKLASKYLHV-GYIVPPapeksivgmtKVKVGKEDSsstEF 90

                          90       100
                  ....*....|....*....|....*.
gi 1034596582 741 VEERRKQLQNYL-RSVMNKVIQMVPE 765
Cdd:cd07282    91 VEKRRAALERYLqRTVKHPTLLQDPD 116

RUN domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also called Rab4-interacting protein related, is a novel embryonic factor that contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. It is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. This model represents the RUN domain of RUFY2.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 122 VGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEErSSMLPTMAAGLNSI 181
Cdd:cd17695    93 LGRARAWLRLALMQKKLADYLRCLIIRRDLLSEFYEYHALMMEEE-GAVIVGLLVGLNVI 151

The phosphoinositide binding Phox Homology domain of Sorting Nexin 25; 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. The function of SNX25 is not yet known. It has been found in exosomes from human malignant pleural effusions. SNX25 shows the same domain architecture as SNX13 and SNX14, containing 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 699 WNIYRRYTEFRSLHHKLQNKYPQVRAYNFP--PKKAIGNKDAKFVEERRKQLQNYLRSVM 756
Cdd:cd06878    50 WVVTRKLSEFHDLHRKLKECSSWLKKVELPslSKKWFKSIDKKFLDKSKNQLQKYLQFIL 109

RUN domain found in Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN) and similar proteins; RUBCN, also called rubicon, or beclin-1 associated RUN domain containing protein (Baron), is part of a Beclin-1-Vps34-containing autophagy complex. It negatively regulates endosome maturation and degradative endocytic trafficking and impairs autophagosome maturation process. It is also an important negative regulator of the innate immune response, enhances viral replication and may play a role in viral immune evasion. This model contains the RUN domain of RUBCN.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582  55 LCAQFEAVLQHGLKRSRGLaltaaaikqaagfasktETEPVFWYYVKEV--------LNKHELQRFYSLRHIASDVGRgr 126
Cdd:cd17686    24 LCRAVENILQHGLKEFQGL-----------------NKEIDDWEFVQGLrwlqptlaPSIEQQSRSSPSESEVSDKGR-- 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1034596582 127 AWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVMDEERSSML 171
Cdd:cd17686    85 LWLRQSLQQHCLSSQLQWLVSDKELLRKYYEDEAFLRQEGYATAL 129

The phosphoinositide binding Phox Homology domain of uncharacterized SNX19-like plant proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized plant proteins containing an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some sorting nexins (SNXs). This is the same domain architecture found in SNX19. SNX13 and SNX14 also contain these three domains but also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. 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. 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 1034596582 688 YQVY-IRIKDDE---WNIYRRYTEFRSLHHKLQnKYPQVrAYNFPPKKAIGNK-DAKFVEERRKQLQNYLRSVMnkVIQM 762
Cdd:cd06872    18 FAVYsVAVTDNEnetWVVKRRFRNFETLHRRLK-EVPKY-NLELPPKRFLSSSlDGAFIEERCKLLDKYLKDLL--VIEK 93

                  ....*
gi 1034596582 763 VPEFA 767
Cdd:cd06872    94 VAESH 98

The phosphoinositide binding Phox Homology Domain of the Alpha Isoform of Class II Phosphoinositide 3-Kinases; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C-terminus. The class II alpha isoform, PI3K-C2alpha, plays key roles in clathrin assembly and clathrin-mediated membrane trafficking, insulin signaling, vascular smooth muscle contraction, and the priming of neurosecretory granule exocytosis. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034596582 674 SVFLRGKAANAFHVYQVYIRI----KDDEWNIYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKAIGNKDAKFVEERRK-QL 748
Cdd:cd07289     3 SVFTYHKRYNPDKHYIYVVRIlregQIEPSFVFRTFDEFQELHNKLSILFPLWKLPGFPNKMVLGRTHIKDVAAKRKvEL 82

                  ....*....
gi 1034596582 749 QNYLRSVMN 757
Cdd:cd07289    83 NSYIQSLMN 91

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 1034596582 686 HVYQVYIRIKDDEWN-----IYRRYTEFRSLHHKLQNKYPQVRAYNFPPKKaignkdaKFVEER-RKQLQNYLRSVMNkv 759
Cdd:cd06869    32 HHYEFIIRVRREGEEyrtiyVARRYSDFKKLHHDLKKEFPGKKLPKLPHKD-------KLPREKlRLSLRQYLRSLLK-- 102

                          90
                  ....*....|.
gi 1034596582 760 iqmVPEFAASP 770
Cdd:cd06869   103 ---DPEVAHSS 110

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 1034596582 668 INVWIPSVFL-RGKAANAFHVYQVYIRIKDDEWNIYRRYTEFRSLHHKLQNKYpqvRAYNFPPKKaIGNKDAKFVEERRK 746
Cdd:cd06880     1 IEVSIPSYRLeVDESEKPYTVFTIEVLVNGRRHTVEKRYSEFHALHKKLKKSI---KTPDFPPKR-VRNWNPKVLEQRRQ 76

                          90       100
                  ....*....|....*....|..
gi 1034596582 747 QLQNYLRSVM--NKVIQMVPEF 766
Cdd:cd06880    77 GLEAYLQGLLkiNELPKQLLDF 98

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1034596582 701 IYRRYTEFRSLHHKLQNKyPQVRAY--NFPPKK-----AIGNKDAKFVEERRKQLQNYLRSVMNkviqmVPEFAASP 770
Cdd:cd06893    53 VNRRFREFLTLQTRLEEN-PKFRKImnVKGPPKrlfdlPFGNMDKDKIEARRGLLETFLRQLCS-----IPEISNSE 123

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15; 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. SNX15 contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) domain. It 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 1034596582 701 IYRRYTEFRSLHHKLQNKYPQV--RAYNFPP---KKAIGNKDAKFVEERRKQLQNYLRSVMNkviqmVPEFAASPkketl 775
Cdd:cd07288    40 VWKRYSDLKKLHGELAYTHRNLfrRQEEFPPfprAQVFGRFEAAVIEERRNAAEAMLLFTVN-----IPALYNSP----- 109

                  ....*..
gi 1034596582 776 iQLMPFF 782
Cdd:cd07288   110 -QLKEFF 115

RUN1 domain found in DENN domain-containing protein 5B (DENND5B) and similar proteins; DENND5B, also called Rab6-interacting protein 1 (Rab6IP1)-like protein, functions in membrane trafficking at a crossroads between the Golgi and the endosomal system. It is composed of an N-terminal DENN (Differentially Expressed in Normal and Neoplastic cells) domain followed by two RUN (RPIP8 [RaP2-interacting protein 8], UNC-14, and NESCA [new molecule containing SH3 at the carboxyl terminus]) domains flanking a PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain. This model represents the first RUN domain of DENND5B.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1034596582 107 HELQRFYSLRHIASDVGRGRAWLRCALNEHSLERYLHMLLADRCRLSTFYEDWSFVM-DEERSSML 171
Cdd:cd17691   122 QDMRHIQNMSEIKTDVGRARAWIRLSLEKKLLSQHLKQLLSNQALTKKLYKRYAFLRcEEEKEQFL 187