Aromatic interactions with membrane modulate human BK channel activation

• Published in: eLife 2020-06, Vol.9
• Main Authors: Yazdani, Mahdieh, Zhang, Guohui, Jia, Zhiguang, Shi, Jingyi, Cui, Jianmin, Chen, Jianhan
• Format: Article
• Language: English
• Subjects: allosteric coupling; Allosteric properties; Animals; atomistic simulation; Binding sites; Calcium (intracellular); Calcium - metabolism; Calcium channels (voltage-gated); Cell Membrane - metabolism; Cell Membrane - physiology; channel gating; Electrophysiological Phenomena; Humans; hydrophobic dewetting; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - chemistry; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - metabolism; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - physiology; Large-Conductance Calcium-Activated Potassium Channels - chemistry; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Large-Conductance Calcium-Activated Potassium Channels - physiology; membrane anchoring; Mutagenesis; Potassium; Potassium channels; Potassium conductance; Protein Structure, Tertiary; Proteins; Sensors; Simulation; Structural Biology and Molecular Biophysics; Xenopus laevis
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.55571

Large-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca . The only covalent connection between the cytosolic Ca 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.