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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Ion Channel Gating / physiology*
  • Phosphatidylinositol 4,5-Diphosphate / chemistry*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Protein Binding
  • Protein Domains
  • Structure-Activity Relationship
  • Transient Receptor Potential Channels / chemistry*
  • Transient Receptor Potential Channels / metabolism*
  • Xenopus laevis

Substances

  • Phosphatidylinositol 4,5-Diphosphate
  • Transient Receptor Potential Channels