한빛사논문
Jongdae Won 1,4,7, Jinhyeong Kim 2,7, Jinsung Kim 2,5,7, Juyeon Ko 2,6, Christine Haewon Park 2,6, Byeongseok Jeong 2, Sang-Eun Lee 2, Hyeongseop Jeong 3, Sun-Hong Kim 1, Hyunwoo Park 1, Insuk So 2,* & Hyung Ho Lee 1,*
1Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
2Department of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
3Center for Research Equipment, Korea Basic Science Institute, Cheongju, Republic of Korea.
4Present address: Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
5Present address: Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA, USA.
6Present address: Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
7These authors contributed equally: Jongdae Won, Jinhyeong Kim, Jinsung Kim.
*Corresponding authors: correspondence to Insuk So or Hyung Ho Lee
Abstract
Transient receptor potential (TRP) ion channels have a crucial role as cellular sensors, mediating diverse physical and chemical stimuli. The formation of heteromeric structures expands the functionality of TRP channels; however, their molecular architecture remains largely unknown. Here we present the cryo-electron microscopy structures of the human TRPC1/TRPC4 heteromer in the apo and antagonist-bound states, both consisting of one TRPC1 subunit and three TRPC4 subunits. The heteromer structure reveals a distinct ion-conduction pathway, including an asymmetrically constricted selectivity filter and an asymmetric lower gate, primarily attributed to the incorporation of TRPC1. Through a structure-guided electrophysiological assay, we show that both the selectivity filter and the lower part of the S6 helix participate in deciding overall preference for permeating monovalent cations. Moreover, we reveal that the introduction of one lysine residue of TRPC1 into the tetrameric central cavity is enough to render one of the most important functional consequences of TRPC heteromerization: reduced calcium permeability. Our results establish a framework for addressing the structure–function relationship of the heteromeric TRP channels.
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