A conserved mechanism couples cytosolic domain movements to pore gating in the TRPM2 channel

Tóth, Balázs and Jiang, Yuefeng and Szöllősi, András and Zhang, Zhe and Csanády, László (2024) A conserved mechanism couples cytosolic domain movements to pore gating in the TRPM2 channel. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 121 (46). No. e2415548121. ISSN 0027-8424

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Abstract

Transient Receptor Potential Melastatin 2 (TRPM2) cation channels contribute to immunocyte activation, insulin secretion, and central thermoregulation. TRPM2 opens upon binding cytosolic Ca 2+ and ADP ribose (ADPR). We present here the 2.5 Å cryo-electronmicroscopy structure of TRPM2 from Nematostella vectensis (nvTRPM2) in a lipid nanodisc, complexed with Ca 2+ and ADPR-2′-phosphate. Comparison with nvTRPM2 without nucleotide reveals that nucleotide binding-induced movements in the protein’s three “core” layers deconvolve into a set of rigid-body rotations conserved from cnidarians to man. By covalently crosslinking engineered cysteine pairs we systematically trap the cytosolic layers in specific conformations and study effects on gate opening/closure. The data show that nucleotide binding in Layer 3 disrupts inhibitory intersubunit interactions, allowing rotation of Layer 2 which in turn expands the gate located in Layer 1. Channels trapped in that “activated” state are no longer nucleotide dependent, but are opened by binding of Ca 2+ alone.

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