The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel

Fan Yang, Xian Xiao, Bo Hyun Lee, Simon Vu, Wei Yang, Vladimir Yarov-Yarovoy, Jie Zheng

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4–S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

Original languageEnglish (US)
Article number2879
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Capsaicin
Ion Channels
Chemical activation
activation
Structural Models
closures
bundles
melting points
amino acids
electron microscopy
selectivity
free energy
filters
Cryoelectron Microscopy
TRPV Cation Channels
S 6
Transition Temperature
vanilloid receptor subtype 1
Freezing
Electron microscopy

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel. / Yang, Fan; Xiao, Xian; Lee, Bo Hyun; Vu, Simon; Yang, Wei; Yarov-Yarovoy, Vladimir; Zheng, Jie.

In: Nature Communications, Vol. 9, No. 1, 2879, 01.12.2018.

Research output: Contribution to journalArticle

@article{af5f131e26f7438fa09958b50ec8aca5,
title = "The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel",
abstract = "The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4–S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.",
author = "Fan Yang and Xian Xiao and Lee, {Bo Hyun} and Simon Vu and Wei Yang and Vladimir Yarov-Yarovoy and Jie Zheng",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-05339-6",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel

AU - Yang, Fan

AU - Xiao, Xian

AU - Lee, Bo Hyun

AU - Vu, Simon

AU - Yang, Wei

AU - Yarov-Yarovoy, Vladimir

AU - Zheng, Jie

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4–S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

AB - The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4–S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

UR - http://www.scopus.com/inward/record.url?scp=85050628758&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050628758&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-05339-6

DO - 10.1038/s41467-018-05339-6

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2879

ER -