Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03370-1
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Funding
- Cancer Research UK
- PRISM EU Sixth Framework Program
- MRC
- Wellcome Trust
- TMIC
- Genome Canada
- Canada Foundation for Innovation
- Campus Alberta Innovates Program
- Polish-Swiss Research Program [PSPB-094/2010]
- BBSRC [BB/I013865/1, BB/H019383/1, BB/H024697/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I013865/1, BBS/B/10714, BB/H024697/1, BB/H019383/1] Funding Source: researchfish
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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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