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Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting

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  • Marc Lenoir

    (University of Birmingham, Edgbaston)

  • Cansel Ustunel

    (University of Geneva)

  • Sandya Rajesh

    (University of Birmingham, Edgbaston)

  • Jaswant Kaur

    (University of Birmingham, Edgbaston)

  • Dimitri Moreau

    (University of Geneva)

  • Jean Gruenberg

    (University of Geneva)

  • Michael Overduin

    (University of Alberta)

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.

Suggested Citation

  • Marc Lenoir & Cansel Ustunel & Sandya Rajesh & Jaswant Kaur & Dimitri Moreau & Jean Gruenberg & Michael Overduin, 2018. "Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03370-1
    DOI: 10.1038/s41467-018-03370-1
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