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Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM. | LitMetric

Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM.

Elife

Department of Structural Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.

Published: February 2019

AI Article Synopsis

Article Abstract

Scramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca-bound and Ca-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca-bound state. Additionally, our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414200PMC
http://dx.doi.org/10.7554/eLife.44364DOI Listing

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