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. 2001 Aug 15;358(Pt 1):7–16. doi: 10.1042/0264-6021:3580007

A large family of endosome-localized proteins related to sorting nexin 1.

R D Teasdale 1, D Loci 1, F Houghton 1, L Karlsson 1, P A Gleeson 1
PMCID: PMC1222026  PMID: 11485546

Abstract

Sorting nexin 1 (SNX1), a peripheral membrane protein, has previously been shown to regulate the cell-surface expression of the human epidermal growth factor receptor [Kurten, Cadena and Gill (1996) Science 272, 1008-1010]. Searches of human expressed sequence tag databases with SNX1 revealed eleven related human cDNA sequences, termed SNX2 to SNX12, eight of them novel. Analysis of SNX1-related sequences in the Saccharomyces cerevisiae genome clearly shows a greatly expanded SNX family in humans in comparison with yeast. On the basis of the predicted protein sequences, all members of this family of hydrophilic molecules contain a conserved 70-110-residue Phox homology (PX) domain, referred to as the SNX-PX domain. Within the SNX family, subgroups were identified on the basis of the sequence similarities of the SNX-PX domain and the overall domain structure of each protein. The members of one subgroup, which includes human SNX1, SNX2, SNX4, SNX5 and SNX6 and the yeast Vps5p and YJL036W, all contain coiled-coil regions within their large C-terminal domains and are found distributed in both membrane and cytosolic fractions, typical of hydrophilic peripheral membrane proteins. Localization of the human SNX1 subgroup members in HeLa cells transfected with the full-length cDNA species revealed a similar intracellular distribution that in all cases overlapped substantially with the early endosome marker, early endosome autoantigen 1. The intracellular localization of deletion mutants and fusions with green fluorescent protein showed that the C-terminal regions of SNX1 and SNX5 are responsible for their endosomal localization. On the basis of these results, the functions of these SNX molecules are likely to be unique to endosomes, mediated in part by interactions with SNX-specific C-terminal sequences and membrane-associated determinants.

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Selected References

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  1. Bairoch A., Bucher P., Hofmann K. The PROSITE database, its status in 1997. Nucleic Acids Res. 1997 Jan 1;25(1):217–221. doi: 10.1093/nar/25.1.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barr V. A., Phillips S. A., Taylor S. I., Haft C. R. Overexpression of a novel sorting nexin, SNX15, affects endosome morphology and protein trafficking. Traffic. 2000 Nov;1(11):904–916. doi: 10.1034/j.1600-0854.2000.011109.x. [DOI] [PubMed] [Google Scholar]
  3. Bateman A., Birney E., Durbin R., Eddy S. R., Howe K. L., Sonnhammer E. L. The Pfam protein families database. Nucleic Acids Res. 2000 Jan 1;28(1):263–266. doi: 10.1093/nar/28.1.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bock J. B., Lin R. C., Scheller R. H. A new syntaxin family member implicated in targeting of intracellular transport vesicles. J Biol Chem. 1996 Jul 26;271(30):17961–17965. doi: 10.1074/jbc.271.30.17961. [DOI] [PubMed] [Google Scholar]
  5. Boguski M. S., Lowe T. M., Tolstoshev C. M. dbEST--database for "expressed sequence tags". Nat Genet. 1993 Aug;4(4):332–333. doi: 10.1038/ng0893-332. [DOI] [PubMed] [Google Scholar]
  6. Cherry J. M., Adler C., Ball C., Chervitz S. A., Dwight S. S., Hester E. T., Jia Y., Juvik G., Roe T., Schroeder M. SGD: Saccharomyces Genome Database. Nucleic Acids Res. 1998 Jan 1;26(1):73–79. doi: 10.1093/nar/26.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ekena K., Stevens T. H. The Saccharomyces cerevisiae MVP1 gene interacts with VPS1 and is required for vacuolar protein sorting. Mol Cell Biol. 1995 Mar;15(3):1671–1678. doi: 10.1128/mcb.15.3.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Haft C. R., de la Luz Sierra M., Bafford R., Lesniak M. A., Barr V. A., Taylor S. I. Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Mol Biol Cell. 2000 Dec;11(12):4105–4116. doi: 10.1091/mbc.11.12.4105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Haft C. R., de la Luz Sierra M., Barr V. A., Haft D. H., Taylor S. I. Identification of a family of sorting nexin molecules and characterization of their association with receptors. Mol Cell Biol. 1998 Dec;18(12):7278–7287. doi: 10.1128/mcb.18.12.7278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Horazdovsky B. F., Davies B. A., Seaman M. N., McLaughlin S. A., Yoon S., Emr S. D. A sorting nexin-1 homologue, Vps5p, forms a complex with Vps17p and is required for recycling the vacuolar protein-sorting receptor. Mol Biol Cell. 1997 Aug;8(8):1529–1541. doi: 10.1091/mbc.8.8.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Howard L., Nelson K. K., Maciewicz R. A., Blobel C. P. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J Biol Chem. 1999 Oct 29;274(44):31693–31699. doi: 10.1074/jbc.274.44.31693. [DOI] [PubMed] [Google Scholar]
  12. Jahn R., Südhof T. C. Membrane fusion and exocytosis. Annu Rev Biochem. 1999;68:863–911. doi: 10.1146/annurev.biochem.68.1.863. [DOI] [PubMed] [Google Scholar]
  13. Karlsson L., Péléraux A., Lindstedt R., Liljedahl M., Peterson P. A. Reconstitution of an operational MHC class II compartment in nonantigen-presenting cells. Science. 1994 Dec 2;266(5190):1569–1573. doi: 10.1126/science.7985028. [DOI] [PubMed] [Google Scholar]
  14. Kurten R. C., Cadena D. L., Gill G. N. Enhanced degradation of EGF receptors by a sorting nexin, SNX1. Science. 1996 May 17;272(5264):1008–1010. doi: 10.1126/science.272.5264.1008. [DOI] [PubMed] [Google Scholar]
  15. Lupas A. Prediction and analysis of coiled-coil structures. Methods Enzymol. 1996;266:513–525. doi: 10.1016/s0076-6879(96)66032-7. [DOI] [PubMed] [Google Scholar]
  16. Lupas A., Van Dyke M., Stock J. Predicting coiled coils from protein sequences. Science. 1991 May 24;252(5009):1162–1164. doi: 10.1126/science.252.5009.1162. [DOI] [PubMed] [Google Scholar]
  17. Mellman I. Endocytosis and molecular sorting. Annu Rev Cell Dev Biol. 1996;12:575–625. doi: 10.1146/annurev.cellbio.12.1.575. [DOI] [PubMed] [Google Scholar]
  18. Morton C. J., Campbell I. D. SH3 domains. Molecular 'Velcro'. Curr Biol. 1994 Jul 1;4(7):615–617. doi: 10.1016/s0960-9822(00)00134-2. [DOI] [PubMed] [Google Scholar]
  19. Mu F. T., Callaghan J. M., Steele-Mortimer O., Stenmark H., Parton R. G., Campbell P. L., McCluskey J., Yeo J. P., Tock E. P., Toh B. H. EEA1, an early endosome-associated protein. EEA1 is a conserved alpha-helical peripheral membrane protein flanked by cysteine "fingers" and contains a calmodulin-binding IQ motif. J Biol Chem. 1995 Jun 2;270(22):13503–13511. doi: 10.1074/jbc.270.22.13503. [DOI] [PubMed] [Google Scholar]
  20. Nilsson T., Jackson M., Peterson P. A. Short cytoplasmic sequences serve as retention signals for transmembrane proteins in the endoplasmic reticulum. Cell. 1989 Aug 25;58(4):707–718. doi: 10.1016/0092-8674(89)90105-0. [DOI] [PubMed] [Google Scholar]
  21. Nothwehr S. F., Hindes A. E. The yeast VPS5/GRD2 gene encodes a sorting nexin-1-like protein required for localizing membrane proteins to the late Golgi. J Cell Sci. 1997 May;110(Pt 9):1063–1072. doi: 10.1242/jcs.110.9.1063. [DOI] [PubMed] [Google Scholar]
  22. Opat A. S., Houghton F., Gleeson P. A. Medial Golgi but not late Golgi glycosyltransferases exist as high molecular weight complexes. Role of luminal domain in complex formation and localization. J Biol Chem. 2000 Apr 21;275(16):11836–11845. doi: 10.1074/jbc.275.16.11836. [DOI] [PubMed] [Google Scholar]
  23. Otsuki T., Kajigaya S., Ozawa K., Liu J. M. SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein. Biochem Biophys Res Commun. 1999 Nov 30;265(3):630–635. doi: 10.1006/bbrc.1999.1731. [DOI] [PubMed] [Google Scholar]
  24. Phillips S. A., Barr V. A., Haft D. H., Taylor S. I., Haft C. R. Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking. J Biol Chem. 2000 Nov 20;276(7):5074–5084. doi: 10.1074/jbc.M004671200. [DOI] [PubMed] [Google Scholar]
  25. Ponting C. P. Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains? Protein Sci. 1996 Nov;5(11):2353–2357. doi: 10.1002/pro.5560051122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rost B., Casadio R., Fariselli P., Sander C. Transmembrane helices predicted at 95% accuracy. Protein Sci. 1995 Mar;4(3):521–533. doi: 10.1002/pro.5560040318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rost B. PHD: predicting one-dimensional protein structure by profile-based neural networks. Methods Enzymol. 1996;266:525–539. doi: 10.1016/s0076-6879(96)66033-9. [DOI] [PubMed] [Google Scholar]
  28. Rost B., Sander C. Combining evolutionary information and neural networks to predict protein secondary structure. Proteins. 1994 May;19(1):55–72. doi: 10.1002/prot.340190108. [DOI] [PubMed] [Google Scholar]
  29. Rost B., Sander C. Prediction of protein secondary structure at better than 70% accuracy. J Mol Biol. 1993 Jul 20;232(2):584–599. doi: 10.1006/jmbi.1993.1413. [DOI] [PubMed] [Google Scholar]
  30. Schmid S. L. Clathrin-coated vesicle formation and protein sorting: an integrated process. Annu Rev Biochem. 1997;66:511–548. doi: 10.1146/annurev.biochem.66.1.511. [DOI] [PubMed] [Google Scholar]
  31. Schultz J., Copley R. R., Doerks T., Ponting C. P., Bork P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 2000 Jan 1;28(1):231–234. doi: 10.1093/nar/28.1.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Seaman M. N., McCaffery J. M., Emr S. D. A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J Cell Biol. 1998 Aug 10;142(3):665–681. doi: 10.1083/jcb.142.3.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Simons K., Zerial M. Rab proteins and the road maps for intracellular transport. Neuron. 1993 Nov;11(5):789–799. doi: 10.1016/0896-6273(93)90109-5. [DOI] [PubMed] [Google Scholar]
  34. Thompson J. D., Gibson T. J., Plewniak F., Jeanmougin F., Higgins D. G. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 1997 Dec 15;25(24):4876–4882. doi: 10.1093/nar/25.24.4876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Voos W., Stevens T. H. Retrieval of resident late-Golgi membrane proteins from the prevacuolar compartment of Saccharomyces cerevisiae is dependent on the function of Grd19p. J Cell Biol. 1998 Feb 9;140(3):577–590. doi: 10.1083/jcb.140.3.577. [DOI] [PMC free article] [PubMed] [Google Scholar]

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