Structures and gating mechanism of human TRPM2.

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 conforma

SUBMITTER: Wang L 

PROVIDER: S-EPMC6459600 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature