Structural and Functional Studies on Noxious Stimuli Sensing of the Transient Receptor Potential Ankyrin 1 Channel

Loading...
Thumbnail Image

Date

2021

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

67
views
24
downloads

Abstract

Transient receptor potential channel subfamily A member 1 (TRPA1) is a Ca2+-permeable cation channel that serves as the primary sensor of environmental irritants, noxious substances, and temperature. Many TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. TRPA1 is also a temperature activated channel displaying unique species-specific thermo sensitivity. Preceding this work, however, a mechanistic understanding of electrophile sensing by TRPA1 has been limited by a lack of structural information. Moreover, the mechanism by which TRPA1 sense temperature has been elusive. Using cryo-electron microscopy, we determined the structures of nanodisc-reconstituted human TRPA1 in ligand free state and in complex with the covalent agonists JT010 or BITC at 2.8, 2.9, and 3.1 Å, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive Cys621 in TRPA1 and grant mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work illustrates the fundamental principles of irritant sensing in humans at the molecular level and provides a platform for future drug development targeting TRPA1. Moreover, we determined the cryo-EM structure of rattlesnake TRPA1 in nanodisc-reconstituted condition at 3.3 Å. This structural revealed a novel N-terminal ankyrin repeat domain that was not resolved in previous structures. Our structural and functional studies on rattlesnake TRPA1 provides a framework in understanding the principles of thermo sensitivity in TRPA1.

Department

Description

Provenance

Citation

Citation

Suo, Yang (2021). Structural and Functional Studies on Noxious Stimuli Sensing of the Transient Receptor Potential Ankyrin 1 Channel. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23029.

Collections


Except where otherwise noted, student scholarship that was shared on DukeSpace after 2009 is made available to the public under a Creative Commons Attribution / Non-commercial / No derivatives (CC-BY-NC-ND) license. All rights in student work shared on DukeSpace before 2009 remain with the author and/or their designee, whose permission may be required for reuse.