Mutant T421A Suggests Its Hydrogen Bond In S1 Helix Is The Key To Secure The Movement Of S4 Helix

hERG(Human ether-a-go-go-related gene)is the basis of fast delayed rectifier IKr,which ends the systole of the heart and plays an important role in the repolarization of the heart.Loss of function of hERG channels can lead to LQT2 and SQTS,each of which may lead to cardiac tip torsion and sudden death.However,as an important part of the VSD region of hERG channel,there were few studies on the S1 chain.Some studies have shown that the mutation of 421 site in S1 chain from threonine to alanine will lead to a significant voltage dependent super shift of channel activation,but the mechanism is still unclear.Whether there is a fixed structure at T421 site in S1,which can directly affect the movement of S4 chain.In this paper,the effects of charged residues in S1 chain,hydrogen bond with T421 and charged residues in S4 chain on hERG gated channel were discussed.The results showed that T421 interacted with K407,D411,V418 on S1 and K538 on S4,and T421 A / D411 C,T421A /V418 A and T421 A / K538 D slowed down the activation and accelerated the deactivation,The interaction between K538 was conducive to maintaining the open state of the channel,that is,T421 may form an anchor structure with D411 and V418,and connect with K538.This structure can limit the range of activity of S4,and shorten the distance between S1 and S4,so that T421 site can contact with S4 chain.When the site in this structure was mutated,the stability of the structure was destroyed,and the distance between S1 and S4 was widened.As a result,the channel tended to be closed,and the voltage dependence of T421 site was shifted to the right.