Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase

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Abstract

From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca²⁺ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl^- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca²⁺-activated Cl^- channel convert it into a robust scramblase.

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Tao Jiang

Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States

For correspondence
jiang57@illinois.edu

Competing interests
The authors declare that no competing interests exist.
Kuai Yu

Department of Cell Biology, Emory University School of Medicine, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
H Criss Hartzell

Department of Cell Biology, Emory University School of Medicine, Atlanta, United States

For correspondence
criss.hartzell@emory.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3393-1528
Emad Tajkhorshid

Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States

For correspondence
emad@life.illinois.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8434-1010

Funding

National Institutes of Health (R01-GM086749)

Emad Tajkhorshid

National Institutes of Health (U54- GM087519)

Emad Tajkhorshid

National Institutes of Health (P41-GM104601)

Emad Tajkhorshid

National Institutes of Health (R01-EY0114852)

H Criss Hartzell

National Institutes of Health (R01-AR067786)

H Criss Hartzell

National Science Foundation (MCA06N060)

Emad Tajkhorshid

National Institutes of Health (R01-GM123455)

Emad Tajkhorshid

Muscular Dystrophy Association (Research Grant)

H Criss Hartzell

National Centre for Supercomputing Applications (Blue Waters)

Emad Tajkhorshid

This research is supported by grants from the National Institutes of Health R01-GM086749, R01-GM123455, U54- GM087519, and P41-GM104601 to ET, and R01-EY0114852 and R01-AR067786 to HCH, and a grant from the Muscular Dystrophy Foundation to HCH. Simulations in this study have been performed using allocations at National Science Foundation Supercomputing Centers (XSEDE grant number MCA06N060), and at the NCSA Blue Waters.

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