X-ray structure of a calcium-activated TMEM16 lipid scramblase.

TitleX-ray structure of a calcium-activated TMEM16 lipid scramblase.
Publication TypeJournal Article
Year of Publication2014
AuthorsBrunner, J. D., N. K. Lim, S. Schenck, A. Duerst, and R. Dutzler
JournalNature
Volume516
Issue7530
Pagination207-12
Date Published2014 Dec 11
ISSN1476-4687
KeywordsAmino Acid Sequence, Animals, Anoctamin-1, Binding Sites, Calcium, Chloride Channels, Crystallography, X-Ray, Electric Conductivity, Humans, Hydrophobic and Hydrophilic Interactions, Ion Transport, Lipid Bilayers, Models, Molecular, Molecular Sequence Data, Nectria, Neoplasm Proteins, Phospholipid Transfer Proteins, Protein Multimerization, Protein Structure, Secondary, Protein Subunits
Abstract

The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca(2+)-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca(2+)-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca(2+)-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca(2+) coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl(-) channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca(2+) activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.

DOI10.1038/nature13984
Alternate JournalNature
PubMed ID25383531
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