8SRC

Cryo-EM structure of TRPM2 chanzyme in the presence of Calcium and ADP-ribose

Summary for 8SRC

• Entry DOI: 10.2210/pdb8src/pdb
• EMDB information: 40726 40865 40893
• Descriptor: TRPM2 chanzyme, ADENOSINE-5-DIPHOSPHORIBOSE, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: trpm2 chanzyme, channel-enzyme, transport protein
• Biological source: Salpingoeca rosetta
• Total number of polymer chains: 4
• Total formula weight: 682805.64

Authors

Huang, Y.,Kumar, S.,Lu, W.,Du, J. (deposition date: 2023-05-05, release date: 2024-05-08, Last modification date: 2024-10-30)

Primary citation

Huang, Y.,Kumar, S.,Lee, J.,Lu, W.,Du, J.
Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution.
Nat.Struct.Mol.Biol., 31:1509-1521, 2024

PubMed Abstract: Channel enzymes represent a class of ion channels with enzymatic activity directly or indirectly linked to their channel function. We investigated a TRPM2 chanzyme from choanoflagellates that integrates two seemingly incompatible functions into a single peptide: a channel module activated by ADP-ribose with high open probability and an enzyme module (NUDT9-H domain) consuming ADP-ribose at a remarkably slow rate. Using time-resolved cryogenic-electron microscopy, we captured a complete series of structural snapshots of gating and catalytic cycles, revealing the coupling mechanism between channel gating and enzymatic activity. The slow kinetics of the NUDT9-H enzyme module confers a self-regulatory mechanism: ADPR binding triggers NUDT9-H tetramerization, promoting channel opening, while subsequent hydrolysis reduces local ADPR, inducing channel closure. We further demonstrated how the NUDT9-H domain has evolved from a structurally semi-independent ADP-ribose hydrolase module in early species to a fully integrated component of a gating ring essential for channel activation in advanced species.

PubMed: 38773335
DOI: 10.1038/s41594-024-01316-4

Experimental method

ELECTRON MICROSCOPY (2.92 Å)