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TitleArchitecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium.
Journal, issue, pagesNature, Vol. 562, Issue 7725, Page 145-149, Year 2018
Publish dateSep 24, 2018
AuthorsYihe Huang / Paige A Winkler / Weinan Sun / Wei Lü / Juan Du /
PubMed AbstractTransient 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 ...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 apoptosis. TRPM2 is polymodal and can be activated by a wide range of stimuli, including temperature, oxidative stress and NAD-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca entry across the plasma membrane and Ca release from lysosomes, and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease. Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca-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.
External linksNature / PubMed:30250252
MethodsEM (single particle)
Resolution3.3 - 3.8 Å
Structure data

7999

6drj

EMDB-7999, PDB-6drj:
Structure of TRPM2 ion channel receptor by single particle electron cryo-microscopy, ADPR/Ca2+ bound state
Method: EM (single particle) / Resolution: 3.3 Å

8901

6drk

EMDB-8901, PDB-6drk:
Structure of TRPM2 ion channel receptor by single particle electron cryo-microscopy, Apo state
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-APR:
ADENOSINE-5-DIPHOSPHORIBOSE

ChemComp-CA:
Unknown entry

Source
  • danio rerio (zebrafish)
KeywordsTRANSPORT PROTEIN

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