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Dynamic assembly of the calcium hemostasis modulator 1 channel gates ATP permeation

By Yue Ren, Yang Li, Yaojie Wang, Tianlei Wen, Xuhang Lu, Shenghai Chang, Xing Zhang, Yuequan Shen, Xue Yang

Posted 02 Sep 2021
bioRxiv DOI: 10.1101/2021.01.14.426634

Calcium hemostasis modulator 1 (CALHM1) is a voltage- and Ca2+-gated ATP channel that plays an important role in neuronal signaling. The currently reported CALHM structures are all in an ATP-conducting state, and the gating mechanism of ATP permeation remains elusive. Here, we report three cryo-EM reconstructions of heptameric CALHM1s with ordered or flexible long C-terminal helices and octameric CALHM1 with flexible long C-terminal helices at resolutions of 3.2 [A], 2.9 [A], and 3.5 [A]. Structural analysis revealed that the heptameric CALHM1s are in an ATP nonconducting state in which the pore diameter in the middle is approximately 6.6 [A]. Compared with those inside the octameric CALHM1s, the N-helices inside heptameric CALHM1s are in the "down" position to avoid steric clash with neighboring TM1 helices. MD simulations show that the pore size is significantly increased for ATP permeation during the movement of the N-helix from the "down" position to the "up" position. Therefore, we proposed a mechanism in which the "piston-like" motion of the N-helix drives the dynamic assembly of the CALHM1 channel for ATP permeation.

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