National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
HL153219
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS112363
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS111031
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM129547
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2024 タイトル: Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution. 著者: Yihe Huang / Sushant Kumar / Junuk Lee / Wei Lü / Juan Du / 要旨: 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 ...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.