Coupling Enzymatic Activity and Gating in an Ancient TRPM Chanzyme and Its Molecular Evolution

Authors

Yihe Huang, University of Nebraska-Lincoln and Van Andel Institute
Sushant Kumar, Van Andel Institute
Junuk Lee, Van Andel Institute
Wei Lü, Van Andel InstituteFollow
Juan Du, Van Andel InstituteFollow

ORCID IDs

Kumar https://orcid.org/0000-0002-0317-8520

Lü https://orcid.org/0000-0002-3009-1025

Du https://orcid.org/0000-0003-1467-1203

Document Type

Article

Date of this Version

2024

Citation

Nature Structural and Molecular Biology (2024) 31: 1509–1521

doi: 10.1038/s41594-024-01316-4

Comments

Open access

License: CC BY 4.0

Abstract

Channel enzymes represent a class of ion channels with enzymatic activity directly or indirectly linked to their channel function. We investigated a TRPM2 chanzyme from choanoflagellates that integrates two seemingly incompatible functions into a single peptide: a channel module activated by ADP-ribose with high open probability and an enzyme module (NUDT9-H domain) consuming ADP-ribose at a remarkably slow rate. Using time-resolved cryogenic-electron microscopy, we captured a complete series of structural snapshots of gating and catalytic cycles, revealing the coupling mechanism between channel gating and enzymatic activity. The slow kinetics of the NUDT9-H enzyme module confers a self-regulatory mechanism: ADPR binding triggers NUDT9-H tetramerization, promoting channel opening, while subsequent hydrolysis reduces local ADPR, inducing channel closure. We further demonstrated how the NUDT9-H domain has evolved from a structurally semi-independent ADP-ribose hydrolase module in early species to a fully integrated component of a gating ring essential for channel activation in advanced species.