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Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium
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Journal Article
Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium
2018
Overview
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
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.
Structures of the transient receptor potential melastatin 2 channel in the apo resting (closed) state and in the ADP-ribose/Ca
2+
-bound active (open) state are determined by cryo-electron microscopy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/109
/ 82/16
/ 82/47
/ 82/80
/ 82/83
/ 9/74
/ Adenosine Diphosphate Ribose - chemistry
/ Adenosine Diphosphate Ribose - metabolism
/ Adenosine Diphosphate Ribose - pharmacology
/ Animals
/ Apoproteins - ultrastructure
/ Domains
/ Humanities and Social Sciences
/ Humans
/ Ion Channel Gating - drug effects
/ Ischemia
/ Letter
/ Ligands
/ NAD
/ Neurodegenerative Diseases - drug therapy
/ Proteins
/ Pyrophosphatases - chemistry
/ Ribose
/ Science
/ Signal Transduction - drug effects
/ Transient receptor potential proteins
/ TRPM Cation Channels - chemistry
/ TRPM Cation Channels - metabolism
/ TRPM Cation Channels - ultrastructure
/ Zebrafish Proteins - chemistry
