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

Janine D. Brunner, Novandy K. Lim, Stephan Schenck, Alessia Duerst and Raimund Dutzler ()
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Janine D. Brunner: University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Novandy K. Lim: University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Stephan Schenck: University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Alessia Duerst: University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Raimund Dutzler: University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Nature, 2014, vol. 516, issue 7530, 207-212

Abstract: Abstract The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca2+-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 Ca2+-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 Ca2+-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca2+ 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 Ca2+ activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.

Date: 2014
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DOI: 10.1038/nature13984

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