Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting

Marc Lenoir, Cansel Ustunel, Sandya Rajesh, Jaswant Kaur, Dimitri Moreau, Jean Gruenberg and Michael Overduin ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03370-1

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