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

Wang Zheng(University of Alberta), Ruiqi Cai(University of Alberta), Laura Hofmann(Saarland University), Vasyl Nesin(University of Oklahoma Health Sciences Center), Qiaolin Hu(University of Alberta), Wentong Long(University of Alberta), Mohammad Fatehi(University of Alberta), Xiong Liu(University of Alberta), Shaimaa Hussein(University of Alberta), Tim Kong(University of Alberta), Jingru Li(University of Alberta), Peter E. Light(University of Alberta), Jingfeng Tang(Hubei University of Technology), Veit Flockerzi(Saarland University), Leonidas Tsiokas(University of Oklahoma Health Sciences Center), Xing-Zhen Chen(University of Alberta)
Cell Reports
February 1, 2018
10.1016/j.celrep.2018.01.042
Cited by 49Open Access
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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.

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