Format

Send to

Choose Destination
Nat Commun. 2019 Oct 31;10(1):4972. doi: 10.1038/s41467-019-12865-4.

Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16.

Author information

1
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. gek2009@med.cornell.edu.
2
Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. gek2009@med.cornell.edu.
3
Department of Biochemistry, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA.
4
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA.
5
Research Group for the Neurovascular Unit, Korea Brain Research Institute, Daegu, Republic of Korea.
6
Department of Anesthesiology, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA.
7
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. ala2022@med.cornell.edu.
8
Department of Biochemistry, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. ala2022@med.cornell.edu.
9
Department of Anesthesiology, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. ala2022@med.cornell.edu.
10
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. haw2002@med.cornell.edu.
11
Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. haw2002@med.cornell.edu.

Abstract

Both lipid and ion translocation by Ca2+-regulated TMEM16 transmembrane proteins utilizes a membrane-exposed hydrophilic groove. Several conformations of the groove are observed in TMEM16 protein structures, but how these conformations form, and what functions they support, remains unknown. From analyses of atomistic molecular dynamics simulations of Ca2+-bound nhTMEM16 we find that the mechanism of a conformational transition of the groove from membrane-exposed to occluded from the membrane involves the repositioning of transmembrane helix 4 (TM4) following its disengagement from a TM3/TM4 interaction interface. Residue L302 is a key element in the hydrophobic TM3/TM4 interaction patch that braces the open-groove conformation, which should be changed by an L302A mutation. The structure of the L302A mutant determined by cryogenic electron microscopy (cryo-EM) reveals a partially closed groove that could translocate ions, but not lipids. This is corroborated with functional assays showing severely impaired lipid scrambling, but robust channel activity by L302A.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center