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

作者：Zheng, Wang; Cai, Ruiqi; Hofmann, Laura; Nesin, Vasyl; Hu, Qiaolin; Long, Wentong; Fatehi, Mohammad; Liu, Xiong; Hussein, Shaimaa; Kong, Tim; Li, Jingru; Light, Peter E.; Tang, Jingfeng^*; Flockerzi, Veit; Tsiokas, Leonidas; Chen, Xing-Zhen^*

来源：Cell Reports, 2018, 22(6): 1560-1573.

DOI：10.1016/j.celrep.2018.01.042

• ION-CHANNEL
• PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE
• ELECTRON CRYOMICROSCOPY
• PHOSPHOLIPASE-C
• ACTIVATION
• RECEPTOR
• INHIBITION
• MECHANISMS
• PKD2
• PHOSPHOINOSITIDES

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.

• 出版日期2018-2-6
• 单位湖北工业大学