Key result
Scrambling the C-linker sequence of BK channels significantly altered the voltage required for half activation, demonstrating that nonspecific interactions with the membrane directly modulate activation.
Why the study?
The role of the 15-residue C-linker connecting the cytosolic Ca 2+ sensing domain and transmembrane domains in BK channel activation remained to be determined.
The C-linker in BK channels is not merely a passive spring but directly modulates channel activation through nonspecific membrane interactions, acting as an integral component of the sensing apparatus.
Large-conductance potassium (BK) channels are transmembrane (TM) proteins that can be synergistically and independently activated by membrane voltage and intracellular Ca 2+ . The only covalent connection between the cytosolic Ca 2+ sensing domain and the TM pore and voltage sensing domains is a 15-residue "C-linker". To determine the linker's role in 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. Combing 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 also suggest that covalent linkers could directly modulate TM protein function and should be considered an integral component of the sensing apparatus.
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Yazdani et al. (2020) studied BK channel activation. C-linker sequence scrambling mutations vs. Wild-type hSlo1 BK channels was evaluated on Voltage required for half activation (V0.5). Scrambling the C-linker sequence of BK channels significantly altered the voltage required for half activation, demonstrating that nonspecific interactions with the membrane directly modulate activation.
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