Structures and gating mechanism of human TRPM2

Area of Science:

• Molecular biology
• Structural biology
• Biochemistry

Background:

• Transient receptor potential (TRP) melastatin 2 (TRPM2) is a crucial cation channel implicated in various diseases.
• TRPM2 activation is dependent on adenosine diphosphate (ADP)-ribose (ADPR) binding to its C-terminal NUDT9 homology (NUDT9H) domain and the presence of calcium (Ca2+).

Purpose of the Study:

• To elucidate the molecular mechanism of TRPM2 channel gating by ADPR and Ca2+.
• To provide structural insights into the activation process of TRPM2.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structures of human TRPM2.
• Structures were obtained for TRPM2 in its apo state, bound to ADPR, and bound to both ADPR and Ca2+.

Main Results:

• The NUDT9H domain interacts with the N-terminal TRPM homology region (MHR1/2/3) in the apo state.
• ADPR binding induces conformational changes, including MHR1/2 rotation and disruption of intersubunit interactions.
• Ca2+ binding further stabilizes transmembrane helices and the TRP helix, leading to pore opening.

Conclusions:

• The study provides a detailed molecular explanation for the concerted gating of TRPM2 by ADPR and Ca2+.
• These findings offer valuable insights into the gating mechanisms of other TRP channels.