the s4–s5 linker acts as a signal integrator for herg k+ channel activation and deactivation gatings4-s5链接器作为信号积分器herg k +通道的激活和解除激活控制.pdfVIP

The S4–S5 Linker Acts as a Signal Integrator for hERG K+ Channel Activation and Deactivation Gating 1,2,3 1 1 1,3 2,4 Chai Ann Ng , Matthew D. Perry , Peter S. Tan , Adam P. Hill , Philip W. Kuchel , Jamie I. Vandenberg1,2,3* 1 Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, 2 School of Molecular Biosciences, University of Sydney, Sydney, New South Wales, Australia, 3 St Vincent’s Clinical School, University of New South Wales, New South Wales, Australia, 4 Mechanistic Systems-biology NMR Group, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Singapore Abstract ` + Human ether-a-go-go-related gene (hERG) K channels have unusual gating kinetics. Characterised by slow activation/ deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4–S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4–S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4–S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4–S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement