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Dev Cell. 2017 Nov 20;43(4):522-529.e4. doi: 10.1016/j.devcel.2017.10.019.

A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch.

Author information

1
Department of Molecular Pharmacology & Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
2
University of Geneva, Section of Pharmaceutical Sciences, 1206 Geneva, Switzerland.
3
Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
4
Department of Molecular Pharmacology & Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
5
University of Geneva, Section of Pharmaceutical Sciences, 1206 Geneva, Switzerland. Electronic address: oscar.vadas@unige.ch.
6
Department of Molecular Pharmacology & Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany. Electronic address: haucke@fmp-berlin.de.

Abstract

Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) at endocytic sites. Structural, biochemical, and cell biological data show that SNX9 is autoinhibited in solution. Binding to PI(3,4)P2 via its PX-BAR domain, and concomitant association with AP2 via sequences in the linker region, releases SNX9 autoinhibitory contacts to enable membrane constriction. Our results reveal a mechanism for restricting the latent membrane remodeling activity of BAR domain proteins to allow spatiotemporal coupling of membrane constriction to the progression of the endocytic pathway.

KEYWORDS:

BAR domain proteins; NMR spectroscopy; endocytosis; hydrogen-deuterium exchange mass spectrometry (HDX-MS); membrane remodeling; phosphoinositides

PMID:
29161595
DOI:
10.1016/j.devcel.2017.10.019
[Indexed for MEDLINE]
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