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Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting

Lenoir, Marc, Ustunel, Cansel, Rajesh, Sandya, Kaur, Jaswant, Moreau, Dimitri, Gruenberg, Jean, Overduin, Michael·2018·Nature Communications
DOI 10.1038/s41467-018-03370-1PMC PMC5843628
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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.

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  • The model indicates that S38 phosphorylation would prevent ligand binding by blocking inositol 3-phosphate entry and thereby fulfill the function of a PIP-stop motif similar to Ser72 of SNX3.

    “the model indicates that S38 phosphorylation would prevent ligand binding by blocking inositol 3-phosphate entry and thereby fulfill the function of a PIP-stop motif similar to Ser72 of SNX3 (34).”

    From Phosphorylation of SNX17 impedes activation of Retriever-mediated sorting (2025) · cites this paper as [34]

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Metadata

Authors
Lenoir, M., Ustunel, C., Rajesh, S., Kaur, J., Moreau, D., Gruenberg, J., & Overduin, M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-03-08
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-03370-1
PMC
PMC5843628
Cited by
49
References
2
Language
en
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