|Title||X-ray structure of a calcium-activated TMEM16 lipid scramblase.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Brunner, J. D., N. K. Lim, S. Schenck, A. Duerst, and R. Dutzler|
|Date Published||2014 Dec 11|
|Keywords||Amino 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|
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.
X-ray structure of a calcium-activated TMEM16 lipid scramblase.