Autoinhibition of TRPV6 Channel and Regulation by PIP2
Ruiqi Cai,
Xiong Liu,
Rui Zhang,
Laura Hofmann,
Wang Zheng,
Md Ruhul Amin,
Lingyun Wang,
Qiaolin Hu,
Ji-Bin Peng,
Marek Michalak,
Veit Flockerzi,
Declan W. Ali,
Xing-Zhen Chen,
Jingfeng Tang
Affiliations
Ruiqi Cai
National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China; Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
Xiong Liu
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
Rui Zhang
National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China
Laura Hofmann
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany
Wang Zheng
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
Md Ruhul Amin
Department of Biological Sciences, Biological Sciences Building, University of Alberta, T6G 2E9 Edmonton, AB, Canada
Lingyun Wang
Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Qiaolin Hu
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
Ji-Bin Peng
Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Marek Michalak
Membrane Protein Disease Research Group, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
Veit Flockerzi
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany
Declan W. Ali
Department of Biological Sciences, Biological Sciences Building, University of Alberta, T6G 2E9 Edmonton, AB, Canada
Xing-Zhen Chen
Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Corresponding author
Jingfeng Tang
National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China; Corresponding author
Summary: Transient receptor potential vanilloid 6 (TRPV6), a calcium-selective channel possessing six transmembrane domains (S1-S6) and intracellular N and C termini, plays crucial roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. The TRPV6 function and regulation remain poorly understood. Here we show that the TRPV6 intramolecular S4-S5 linker to C-terminal TRP helix (L/C) and N-terminal pre-S1 helix to TRP helix (N/C) interactions, mediated by Arg470:Trp593 and Trp321:Ile597 bonding, respectively, are autoinhibitory and are required for maintaining TRPV6 at basal states. Disruption of either interaction by mutations or blocking peptides activates TRPV6. The N/C interaction depends on the L/C interaction but not reversely. Three cationic residues in S5 or C terminus are involved in binding PIP2 to suppress both interactions thereby activating TRPV6. This study reveals “PIP2 - intramolecular interactions” regulatory mechanism of TRPV6 activation-autoinhibition, which will help elucidating the corresponding mechanisms in other TRP channels.
