Functions of Sorting Nexin 17 Domains and Recognition Motif for P-selectin Trafficking

J Mol Biol. 2005 Apr 8;347(4):813-25. doi: 10.1016/j.jmb.2005.02.004.

Abstract

SNX17 is a member of the sorting nexin family (SNX), a group of hydrophilic proteins whose common characteristic property is a phox homology (PX) domain. The PX domain directs SNXs to phosphatidylinositides containing membranes of the endosomal compartment, where the SNXs are involved in the sorting of transmembrane proteins. SNX17 is known to interact with P-selectin and the LDL receptor family. Here, we report that the PX domain of SNX17 specifically binds to phosphatidylinositol 3-phosphate-containing membranes. The functional part of SNX17 that binds P-selectin or Patched (PTCH) consists of a truncated FERM domain and a unique C terminus together (FC-unit). In a yeast two-hybrid analysis a putative recognition motif for the FC-unit was revealed within P-selectin as FxNaa(F/Y). When HepG2 cells overexpress P-selectin together with SNX17, SNX17 changes its distribution from early endosomes to lysobisphosphatidic acid-containing late endosomes. Furthermore, overexpressed SNX17 restrains P-selectin in the outer membrane of the late endosomal compartment, thus preventing the normal lysosomal accumulation of P-selectin. These results suggest that the PX domain is necessary for the intracellular localisation, while the FC-unit is required for cargo recognition. We hypothesise that the expression level of SNX17 may regulate the lysosomal degradation, at least for P-selectin, by suppressing its entry into the inner vesicles of the multi-vesicular bodies (MVBs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cricetinae
  • Endosomes / metabolism
  • Gene Expression
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • P-Selectin / chemistry
  • P-Selectin / genetics
  • P-Selectin / metabolism*
  • Phosphatidylinositol Phosphates / pharmacology
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Substrate Specificity
  • Vesicular Transport Proteins / chemistry*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • Carrier Proteins
  • P-Selectin
  • Phosphatidylinositol Phosphates
  • Vesicular Transport Proteins
  • phosphatidylinositol 3-phosphate