Darwin, mais complexidade: canais de membrana mostram especificidade

quinta-feira, agosto 30, 2018

Hydrophobic gating in BK channels

Zhiguang Jia, Mahdieh Yazdani, Guohui Zhang, Jianmin Cui & Jianhan Chen 

Nature Communications volume 9, Article number: 3408 (2018


Abstract

The gating mechanism of transmembrane ion channels is crucial for understanding how these proteins control ion flow across membranes in various physiological processes. Big potassium (BK) channels are particularly interesting with large single-channel conductance and dual regulation by membrane voltage and intracellular Ca2+. Recent atomistic structures of BK channels failed to identify structural features that could physically block the ion flow in the closed state. Here, we show that gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation. Importantly, the dry pore remains physically open and is readily accessible to quaternary ammonium channel blockers. The hydrophobic gating mechanism is also consistent with scanning mutagenesis studies showing that modulation of pore hydrophobicity is correlated with activation properties.




Acknowledgments

All simulations were performed on the pikes GPU cluster housed in the Massachusetts Green High Performance Computing Cluster (MGHPCC). This work was supported by National Institutes of Health Grants R01 HL142301 (to J. Cui and J. Chen), R01 HL126774 (to J. Cui) and R01 GM114694 (to J. Cui).




Author information

Affiliations

Department of Chemistry, University of Massachusetts, Amherst, MA, 01003, USA

Zhiguang Jia, Mahdieh Yazdani & Jianhan Chen

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, MO, 63130, USA

Guohui Zhang & Jianmin Cui

Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, 01003, USA

Jianhan Chen

Contributions

Conception and design of the study: Z.J., M.Y., G.Z., J. Cui, and J. Chen; Performing the simulation and analysis: Z.J. and M.Y.; Analysis and interpretation of data, drafting, and revising the manuscript: Z.J., M.Y., G.Z., J. Cui, and J. Chen.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jianhan Chen.