Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting

Nat Commun. 2018 Mar 8;9(1):993. doi: 10.1038/s41467-018-03370-1.

Abstract

Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This "PIP-stop" releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Membrane / metabolism*
  • Humans
  • Molecular Sequence Data
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphatidylinositols / metabolism*
  • Phospholipids / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Sorting Nexins / chemistry
  • Sorting Nexins / metabolism*
  • trans-Golgi Network / metabolism

Substances

  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Phospholipids
  • SNX3 protein, human
  • Sorting Nexins
  • phosphatidylinositol 3-phosphate