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Gating mechanism of human N-type voltage-gated calcium channel

By Yanli Dong, Yiwei Gao, Shuai Xu, Yuhang Wang, Zhuoya Yu, Yue Li, Bin Li, Bei Yang, Xuejun Cai Zhang, Daohua Jiang, Zhuo Huang, Yan Zhao

Posted 08 Jul 2021
bioRxiv DOI: 10.1101/2021.07.08.451561

N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at the presynaptic terminals in response to action potential and play vital roles in synaptogenesis, neurotransmitter releasing, and nociceptive transmission. Here we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex at resolution of 2.8 [A]. This complex structure reveals how the CaV2.2, {beta}1, and 2{delta}1 subunits are assembled. In our structure, the second voltage-sensing domain (VSD) is stabilized at a resting-state conformation, which is distinct from the other three VSDs of CaV2.2 as well as activated VSDs observed in previous structures of CaV channels. The structure also shows that the intracellular gate formed by S6 helices is closed, and a W-helix from the DII-III linker is determined to act as a blocking-ball that causes closed-state inactivation in CaV2.2. Collectively, our structure provides previously unseen structural insights into fundamental gating mechanisms of CaV channels.

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