Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

  • Cell Rep. 2018 Feb 6;22(6):1560-1573. doi: 10.1016/j.celrep.2018.01.042.
Wang Zheng  1 ,  Ruiqi Cai  2 ,  Laura Hofmann  3 ,  Vasyl Nesin  4 ,  Qiaolin Hu  2 ,  Wentong Long  5 ,  Mohammad Fatehi  5 ,  Xiong Liu  2 ,  Shaimaa Hussein  2 ,  Tim Kong  2 ,  Jingru Li  2 ,  Peter E Light  5 ,  Jingfeng Tang  6 ,  Veit Flockerzi  3 ,  Leonidas Tsiokas  4 ,  Xing-Zhen Chen  7
Affiliations
  • 1. 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.
  • 2. Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
  • 3. Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg 66421, Germany.
  • 4. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • 5. Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • 6. National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China. Electronic address: [email protected].
  • 7. 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. Electronic address: [email protected].
PMID: 29425510 DOI: 10.1016/j.celrep.2018.01.042
Abstract

Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N-C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels.

Keywords
PIP2; TRP; TRP domain; electrophysiology; gating; intramolecular interaction; pre-S1.