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Structure of TRPM2 ion channel receptor by single particle electron cryo-microscopy, ADPR/Ca2+ bound state
Structural highlights
FunctionTRPM2_DANRE Nonselective, voltage-independent cation channel that mediates Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels. Functions as a ligand-gated ion channel. Binding of ADP-ribose to the cytoplasmic N-terminal region causes a conformation change; the channel is primed but still requires Ca(2+) binding to trigger channel opening.[1] Publication Abstract from PubMedTransient 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 apoptosis(1-4). TRPM2 is polymodal and can be activated by a wide range of stimuli(1-7), including temperature, oxidative stress and NAD(+)-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca(2+) entry across the plasma membrane and Ca(2+) release from lysosomes(8), and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease(9-11). Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca(2+)-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. Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium.,Huang Y, Winkler PA, Sun W, Lu W, Du J Nature. 2018 Oct;562(7725):145-149. doi: 10.1038/s41586-018-0558-4. Epub 2018 Sep, 24. PMID:30250252[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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