X-ray structure of a calcium-activated TMEM16 lipid scramblase.
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.
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Janine D
JD
Brunner
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Novandy K
NK
Lim
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Stephan
S
Schenck
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Alessia
A
Duerst
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Raimund
R
Dutzler
D000595:Amino Acid Sequence; D000818:Animals; D000075369:Anoctamin-1; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018118:Chloride Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004553:Electric Conductivity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D017136:Ion Transport / Q000187:drug effects; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055330:Nectria / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics; D009363:Neoplasm Proteins / Q000737:chemistry; D049294:Phospholipid Transfer Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D008051:Lipid Bilayers; D009363:Neoplasm Proteins; D049294:Phospholipid Transfer Proteins; D021122:Protein Subunits; D002118:Calcium