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Nature. 2018 Oct;562(7725):145-149. doi: 10.1038/s41586-018-0558-4. Epub 2018 Sep 24.

Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium.

Author information

1
Van Andel Research Institute, Grand Rapids, MI, USA.
2
Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
3
Janelia Research Campus, Ashburn, VA, USA.
4
Van Andel Research Institute, Grand Rapids, MI, USA. wei.lu@vai.org.
5
Van Andel Research Institute, Grand Rapids, MI, USA. juan.du@vai.org.

Abstract

Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that has an essential role in diverse physiological processes such as core body temperature regulation, immune response and apoptosis1-4. TRPM2 is polymodal and can be activated by a wide range of stimuli1-7, including temperature, oxidative stress and NAD+-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca2+ entry across the plasma membrane and Ca2+ release from lysosomes8, and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease9-11. Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca2+-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. We identify an ADPR-binding site located in the bi-lobed structure of the MHR1/2 domain. Our results provide an insight into the mechanism of activation of the TRPM channel family and define a framework for the development of therapeutic agents to treat neurodegenerative diseases and temperature-related pathological conditions.

PMID:
30250252
DOI:
10.1038/s41586-018-0558-4

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