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XB-ART-55973
Cell Rep January 1, 2018; 22 (6): 1560-1573.

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

Zheng W , Cai R , Hofmann L , Nesin V , Hu Q , Long W , Fatehi M , Liu X , Hussein S , Kong T , Li J , Light PE , Tang J , Flockerzi V , Tsiokas L , Chen XZ .


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.

PubMed ID: 29425510
PMC ID: PMC6483072
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ctrl foxm1 pkd1 pkd2 trpm8 trpv1 wnt9b


Article Images: [+] show captions
References [+] :
Arif Pavel, Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. 2016, Pubmed