Aromatic interactions with membrane modulate human BK channel activation

eLife

Jianmin Cui¹  Guohui Zhang¹  Jingyi Shi¹  Jianhan Chen²  Zhiguang Jia²  Mahdieh Yazdani² 

[1] Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, United States;Department of Chemistry, University of Massachusetts, Amherst, United States;

关键词: membrane anchoring;    atomistic simulation;    allosteric coupling;    channel gating;    hydrophobic dewetting;   

DOI  :  10.7554/eLife.55571

来源: DOAJ

【 摘 要 】

Large-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca2+. The only covalent connection between the cytosolic Ca2+ sensing domain and the TM pore and voltage sensing domains is a 15-residue ‘C-linker’. To determine the linker’s role in human BK activation, we designed a series of linker sequence scrambling mutants to suppress potential complex interplay of specific interactions with the rest of the protein. The results revealed a surprising sensitivity of BK activation to the linker sequence. Combining atomistic simulations and further mutagenesis experiments, we demonstrated that nonspecific interactions of the linker with membrane alone could directly modulate BK activation. The C-linker thus plays more direct roles in mediating allosteric coupling between BK domains than previously assumed. Our results suggest that covalent linkers could directly modulate TM protein function and should be considered an integral component of the sensing apparatus.

【 授权许可】

Unknown