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

Nature. 2014 Dec 11;516(7530):207-12. doi: 10.1038/nature13984. Epub 2014 Nov 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anoctamin-1
  • Binding Sites / genetics
  • Calcium / chemistry
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Chloride Channels / chemistry*
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Crystallography, X-Ray
  • Electric Conductivity
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ion Transport / drug effects
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Nectria / chemistry*
  • Nectria / enzymology
  • Nectria / genetics
  • Neoplasm Proteins / chemistry
  • Phospholipid Transfer Proteins / chemistry*
  • Phospholipid Transfer Proteins / genetics
  • Phospholipid Transfer Proteins / metabolism*
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism


  • ANO1 protein, human
  • Anoctamin-1
  • Chloride Channels
  • Lipid Bilayers
  • Neoplasm Proteins
  • Phospholipid Transfer Proteins
  • Protein Subunits
  • Calcium