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

Yihe Huang, Paige A. Winkler, Weinan Sun, Wei Lü () and Juan Du ()
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Yihe Huang: Van Andel Research Institute
Paige A. Winkler: Van Andel Research Institute
Weinan Sun: Oregon Health & Science University
Wei Lü: Van Andel Research Institute
Juan Du: Van Andel Research Institute

Nature, 2018, vol. 562, issue 7725, 145-149

Abstract: 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.

Keywords: Transient Receptor Potential Melastatin (TRPM2); TRPM2 Channel; ADPR Molecule; Fourier Shell Correlation; Helical Half-turns (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0558-4

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