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Structural basis of Ca-dependent activation and lipid transport by a TMEM16 scramblase.

TitleStructural basis of Ca-dependent activation and lipid transport by a TMEM16 scramblase.
Publication TypeJournal Article
Year of Publication2019
AuthorsFalzone, ME, Rheinberger, J, Lee, B-C, Peyear, T, Sasset, L, Raczkowski, AM, Eng, ET, Di Lorenzo, A, Andersen, OS, Nimigean, CM, Accardi, A
JournalElife
Volume8
Date Published2019 Jan 16
ISSN2050-084X
Abstract

The lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concentration gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca-activated scramblases, but the mechanisms underlying their Ca-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resolution cryo-electron microscopy structures of a fungal scramblase from , afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional experiments, suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.

DOI10.7554/eLife.43229
Alternate JournalElife
PubMed ID30648972
Grant ListR01GM106717 / / National Institute of General Medical Sciences /
2013R1A6A3A03064407 / / National Research Foundation of Korea /
F00316 / / Agouron Institute /
349247 / / Simons Foundation /
GM103310 / / National Institute of General Medical Sciences /
1R01GM124451-02 / / National Institute of General Medical Sciences /
18-BR-01-02 / / Ministry of Science, ICT and Future Planning /
R21NS10451 / / National Institute of Neurological Disorders and Stroke /
18-BR-01-02 / / Korean Ministry of Science /