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Nat Commun. 2018 Aug 14;9(1):3251. doi: 10.1038/s41467-018-05724-1.

Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase.

Author information

1
Department of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
2
Korea Brain Research Institute (KBRI), Daegu, Republic of Korea, 41068.
3
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
4
Institute for Computational Biomedicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
5
Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
6
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. haw2002@physbio-tech.net.
7
Institute for Computational Biomedicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. haw2002@physbio-tech.net.
8
Department of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. ala2022@med.cornell.edu.
9
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. ala2022@med.cornell.edu.
10
Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. ala2022@med.cornell.edu.

Abstract

Members of the TMEM16/ANO family of membrane proteins are Ca2+-activated phospholipid scramblases and/or Cl- channels. A membrane-exposed hydrophilic groove in these proteins serves as a shared translocation pathway for ions and lipids. However, the mechanism by which lipids gain access to and permeate through the groove remains poorly understood. Here, we combine quantitative scrambling assays and molecular dynamic simulations to identify the key steps regulating lipid movement through the groove. Lipid scrambling is limited by two constrictions defined by evolutionarily conserved charged and polar residues, one extracellular and the other near the membrane mid-point. The region between these constrictions is inaccessible to lipids and water molecules, suggesting that the groove is in a non-conductive conformation. A sequence of lipid-triggered reorganizations of interactions between these residues and the permeating lipids propagates from the extracellular entryway to the central constriction, allowing the groove to open and coordinate the headgroups of transiting lipids.

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