Human mutations highlight an intersubunit cation–π bond that stabilizes the closed but not open or inactivated states of TRPV channels

Jinfeng Teng, Andriy Anishkin, Ching Kung, Paul Blount

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

An adequate response of a living cell to the ever-changing environment requires integration of numerous sensory inputs. In many cases, it can be achieved even at the level of a single receptor molecule. Polymodal transient receptor potential (TRP) channels have been shown to integrate mechanical, chemical, electric, and thermal stimuli. Inappropriate gating can lead to pathologies. Among the >60 known TRP vanilloid subfamily (V) 4 mutations that interfere with bone development are Y602C or R616Q at the S4–S5 linker. A cation–π bond between the conservative residues Y602 and R616 of neighboring subunits appears likely in many homologous channel structures in a closed state. Our experiments with TRPV4 mutants indicate that the resting-closed state remains stable while the bond is substituted by a salt bridge or disulfide bond, whereas disruption of the contact by mutations like Y602C or R616Q produces gain-of-function phenotypes when TRPV4 is heterologously expressed in the Xenopus oocyte or yeast. Our data indicate that the Y602–R616 cation–π interactions link the four S4–S5 linker helices together, forming a girdle backing the closed gate. Analogous cation–π bonds and the girdle are seen in many closed TRP channel structures. This girdle is not observed in the cryo-EM structure of amphibian TRPV4 (Protein Data Bank ID code 6BBJ), which appears to be in a different impermeable state—we hypothesize this is the inactivated state.

Original languageEnglish (US)
Pages (from-to)9410-9416
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number19
DOIs
StatePublished - May 7 2019

Keywords

  • Gating
  • Lipids
  • O
  • Pening mechanism
  • TRP channels
  • TRP domain

ASJC Scopus subject areas

  • General

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