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

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-? 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-? interactions link the four S4-S5 linker helices together, forming a girdle backing the closed gate. Analogous cation-? 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.

SUBMITTER: Teng J

PROVIDER: S-EPMC6511060 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Teng Jinfeng J Anishkin Andriy A Kung Ching C Blount Paul P

Proceedings of the National Academy of Sciences of the United States of America 20190422 19

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 ...[more]

PMID: 31010928

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Dataset Information

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

Publications

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

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