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Human sorting nexin-17, PX domain

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PDB Code 3FOG Target Class Phosphoinosotide dependent signalling Target SNX17 Alias KIAA0064, SNX17 Disease Area/Function Date Deposited Dec 30 2008 Authors M.WISNIEWSKA, L.TRESAUGUES, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, M.SIPONEN, ,A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WIKSTROM, H.SCHUELER

About this structure

Sorting nexins (SNXs) are a family of membrane associated proteins characterized by the presence of a phox (PX) homology domain. This domain confers specificity towards phosphoinositides, and targets the SNX proteins to membrane domains enriched in specific phospholipids [1, 2]. Sorting nexin-17 was initially identified as a binding partner for P-selectin [3]. This interaction accelerates P-selectin internalization and inhibits its lysosomal degradation [4]. SNX17 is also a binding partner for several members of the low-density lipoprotein (LDL) receptor family such as LDLR, VLDLR, ApoER2 and LDLR-related protein (LRP) [5]. Recently it was shown that SNX17 interacts with the NPVY motif in the LDL receptor tail [6], and is a part of the cellular sorting machinery that regulates cell surface levels of LRP by promoting its recycling [7].

SNX17 consists of an N-terminal PX domain, followed by a B41 (band 4.1 or FERM) domain. Here we present the crystal structure of the PX domain at 2.8 Å resolution. The structure was solved by molecular replacement using MOLREP with the cytokine-independent survival kinase CISK-PX (1XTE) as a search model. The asymmetric unit consisted of one polypeptide chain. The overall fold of the SNX17-PX domain is composed of a β-sheet with three antiparallel β-strands and a helical subdomain consisting of three α-helices. Coordinates and structure factors have been deposited in the PDB with accession code 3FOG.

References

  1. Kanai F., Liu H., Field S.J., Akbary H., Matsuo T., Brown G.E., Cantley L.C. and Yaffe M.B. (2001) The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat Cell Biol 3: 675–678.
  2. Cheever M.L., Sato T.K., de Beer T., Kutateladze T.G., Emr S.D. and Overduin M. (2001) Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nat Cell Biol 3: 613–618.
  3. Florian V., Schluter T. and Bohnensack R. (2001) A new member of the sorting nexin family interacts with the C-terminus of P-selectin. Biochem Biophys Res Commun 281: 1045–1050.
  4. Williams R., Schluter T., Roberts M.S., Knauth P., Bohnensack R. and Cutler D.F. (2004) Sorting nexin 17 accelerates internalization yet retards degradation of P-selectin. Mol Biol Cell 15: 3095–3105.
  5. Stockinger W., Sailler B., Strasser V., Recheis B., Fasching D., Kahr L., Schneider W.J. and Nimpf J. (2002) The PX-domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor. EMBO J 21: 4259–4267.
  6. Burden J.J., Sun X.M., Garcia A.B. and Soutar A.K. (2004) Sorting motifs in the intracellular domain of the low density lipoprotein (LDL) receptor interact with a novel domain of sorting nexin-17. J Biol Chem 279: 16237–16245.
  7. van Kerkof P., Lee J., McCormick L., Tetrault E., Lu W., Schoenfish M., Oorschot V., Strous G.J., Klumperman J. and Bu G. (2005) Sorting nexin 17 facilitates LRP recycling in the early endosome. EMBO J 24: 2851-2861.