Structures and gating mechanism of human TRPM2

Science. 2018 Dec 21;362(6421):eaav4809. doi: 10.1126/science.aav4809.

Longfei Wang ^# ¹ ², Tian-Min Fu ^# ³ ², Yiming Zhou ⁴ ⁵, Shiyu Xia ¹ ², Anna Greka ⁴ ⁵, Hao Wu ³ ²

Affiliations

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. tianmin.fu@childrens.harvard.edu wu@crystal.harvard.edu.
4 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
5 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
# Contributed equally.

PMID: 30467180 DOI: 10.1126/science.aav4809

Abstract

Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)-ribose (ADPR), and both ADPR and calcium (CA²⁺) are required for TRPM2 activation. Here we report cryo-electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and CA²⁺ NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of CA²⁺ further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and CA²⁺ and provide insights into the gating mechanism of Other TRP channels.

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