Cryo-EM structure of TMEM63C suggests it functions as a monomer

Yuqi Qin; Daqi Yu; Dan Wu; Jiangqing Dong; William Thomas Li; Chang Ye; Kai Chit Cheung; Yingyi Zhang; Yun Xu; YongQiang Wang; Yun Stone Shi; Shangyu Dang

doi:10.1038/s41467-023-42956-2

Cryo-EM structure of TMEM63C suggests it functions as a monomer

Nat Commun. 2023 Nov 9;14(1):7265. doi: 10.1038/s41467-023-42956-2.

Authors

Yuqi Qin^#¹, Daqi Yu^#¹, Dan Wu^#², Jiangqing Dong^#¹, William Thomas Li¹, Chang Ye², Kai Chit Cheung¹, Yingyi Zhang³, Yun Xu², YongQiang Wang⁴, Yun Stone Shi^{5

6}, Shangyu Dang^{7

8

9}

Affiliations

¹ Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
² State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital Affiliated to Medical School, Nanjing University, Nanjing, 210032, China.
³ Biological Cryo-EM Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
⁴ Howard Hughes Medical Institute, University of California, San Francisco, CA, 94158, USA. yongqiang.wang@ucsf.edu.
⁵ State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital Affiliated to Medical School, Nanjing University, Nanjing, 210032, China. shiyun@gdiist.cn.
⁶ Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, 519031, China. shiyun@gdiist.cn.
⁷ Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. sdang@ust.hk.
⁸ Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China. sdang@ust.hk.
⁹ HKUST-Shenzhen Research Institute, Nanshan, Shenzhen, 518057, China. sdang@ust.hk.

^# Contributed equally.

Abstract

The TMEM63 family proteins (A, B, and C), calcium-permeable channels in animals that are preferentially activated by hypo-osmolality, have been implicated in various physiological functions. Deficiency of these channels would cause many diseases including hearing loss. However, their structures and physiological roles are not yet well understood. In this study, we determine the cryo-electron microscopy (cryo-EM) structure of the mouse TMEM63C at 3.56 Å, and revealed structural differences compared to TMEM63A, TMEM63B, and the plant orthologues OSCAs. Further structural guided mutagenesis and calcium imaging demonstrated the important roles of the coupling of TM0 and TM6 in channel activity. Additionally, we confirm that TMEM63C exists primarily as a monomer under physiological conditions, in contrast, TMEM63B is a mix of monomer and dimer in cells, suggesting that oligomerization is a regulatory mechanism for TMEM63 proteins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium Channels* / metabolism
Calcium* / metabolism
Cryoelectron Microscopy
Mice
Osmolar Concentration

Substances

Calcium
Calcium Channels