Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation

Abstract
Data availability
Article and author information
Metrics

Abstract

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca²⁺-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca²⁺, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here we present the ~3Å resolution electron cryo-microscopy structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca²⁺-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca²⁺ selectivity and larger conductance. The intracellular Ca²⁺ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca²⁺. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2.

Data availability

Cryo-EM density map of nvTRPM2 has been deposited in the electron microscopy data bank (EMDB) under accession code EMD-7542. Atomic coordinates of nvTRPM2 have been deposited in the protein data bank (PDB) under accession code: 6CO7.

The following data sets were generated

1. Csanády et al
(2018) Cryo-EM density map of nvTRPM2
EMD-7542.

https://www.ebi.ac.uk/pdbe/emdb/
1. Csanády et al
(2018) Atomic coordinates of nvTRPM2
6CO7.

https://www.rcsb.org/

Article and author information

Author details

Zhe Zhang

Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States

For correspondence
zzhang01@mail.rockefeller.edu

Competing interests
No competing interests declared.
Balázs Tóth

Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

Competing interests
No competing interests declared.
Andras Szollosi

Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-5570-4609
Jue Chen

Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-2075-4283
László Csanády

Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

For correspondence
csanady.laszlo@med.semmelweis-univ.hu

Competing interests
László Csanády, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-6547-5889

Funding

Howard Hughes Medical Institute (International Early Career Scientist grant)

László Csanády

Magyar Tudományos Akadémia (Lendület grant LP2017-14/2017)

László Csanády

Charles H. Revson Foundation (Charles H. Revson fellowship in Biomedical Science)

Zhe Zhang

Ministry of Human Capacities of Hungary (ÚNKP-17-4 New National Excellence Program)

Balázs Tóth

Howard Hughes Medical Institute (HHMI Investigator)

Jue Chen

Magyar Tudományos Akadémia (János Bolyai Research Fellowship)

Andras Szollosi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Semmelweis University (last approved 06-30-2016, expiration 06-30-2021).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.