4.8 Article

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

期刊

CELL REPORTS
卷 22, 期 6, 页码 1560-1573

出版社

CELL PRESS
DOI: 10.1016/j.celrep.2018.01.042

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资金

  1. Natural Sciences and Engineering Research Council of Canada (NSERC) [RES0012281]
  2. National Natural Science Foundation of China [81570648, 81602448]
  3. Deutsche Forschungsgemeinschaft (DFG) [Sonderforschungsbereich/Transregio 152]
  4. NIH [AR64211, DK59599]
  5. Alberta Innovates-Doctoral Graduate Student Scholarship
  6. NSERC International Research Training Group Studentship
  7. International Research Training Group (DFG) [1830]

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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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