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Cited by 16Calcium signaling and nucleotide metabolismIon Channels and ReceptorsIon channel regulation and function

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Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution

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Huang, Yihe, Kumar, Sushant, Lee, Junuk, Lü, Wei, Du, Juan·2024·Nature Structural & Molecular Biology
DOI 10.1038/s41594-024-01316-4PMC PMC11479946

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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.

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Metadata

Authors
Huang, Y., Kumar, S., Lee, J., Lü, W., & Du, J.
Affiliations
  • University of Nebraska–Lincoln (US)
  • Van Andel Institute (US)
Corresponding author
  • Lü, Wei
  • Du, Juan
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2024-05-21
Volume
31
Issue
10
Pages
1509-1521
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-024-01316-4
PMC
PMC11479946
OpenAlex
W4398183797
Cited by
16
References
1
Citations by year
2026: 5 · 2025: 7 · 2024: 3
FWCI
4.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • Lincoln (University of Nebraska) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL153219)
  • National Institute of General Medical Sciences (U24GM129547)
  • National Institute of Neurological Disorders and Stroke (R01NS112363, R01NS111031, R01NS129804)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
ADP-ribose, channel gating, choanoflagellates, molecular evolution, tetramerization, gating ring, ADP-ribose binding, cryo-electron microscopy

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