PUBLICATION
Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium
- Authors
- Huang, Y., Winkler, P.A., Sun, W., Lü, W., Du, J.
- ID
- ZDB-PUB-180927-5
- Date
- 2018
- Source
- Nature 562(7725): 145-149 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adenosine Diphosphate Ribose/chemistry
- Adenosine Diphosphate Ribose/metabolism
- Adenosine Diphosphate Ribose/pharmacology*
- Animals
- Apoproteins/chemistry
- Apoproteins/metabolism
- Apoproteins/ultrastructure
- Binding Sites
- Calcium/chemistry
- Calcium/metabolism
- Calcium/pharmacology*
- Cryoelectron Microscopy
- Edetic Acid/chemistry
- Humans
- Ion Channel Gating/drug effects
- Ligands
- Models, Molecular
- Neurodegenerative Diseases/drug therapy
- Protein Domains
- Pyrophosphatases/chemistry
- Signal Transduction/drug effects
- TRPM Cation Channels/chemistry
- TRPM Cation Channels/metabolism*
- TRPM Cation Channels/ultrastructure*
- Zebrafish
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism*
- Zebrafish Proteins/ultrastructure*
- PubMed
- 30250252 Full text @ Nature
Citation
Huang, Y., Winkler, P.A., Sun, W., Lü, W., Du, J. (2018) Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium. Nature. 562(7725):145-149.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping