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一种保守的机制将细胞质结构域的运动与 TRPM2 通道的孔门控耦合在一起。

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

机构信息

Department of Biochemistry, Semmelweis University, Budapest H-1094, Hungary.

Molecular Channelopathies Research Group, Hungarian Centre of Excellence for Molecular Medicine - Semmelweis University, Budapest H-1094, Hungary.

出版信息

Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2415548121. doi: 10.1073/pnas.2415548121. Epub 2024 Nov 8.

DOI:10.1073/pnas.2415548121
PMID:39514307
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11573590/
Abstract

Transient Receptor Potential Melastatin 2 (TRPM2) cation channels contribute to immunocyte activation, insulin secretion, and central thermoregulation. TRPM2 opens upon binding cytosolic Ca and ADP ribose (ADPR). We present here the 2.5 Å cryo-electronmicroscopy structure of TRPM2 from (nvTRPM2) in a lipid nanodisc, complexed with Ca 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 alone.

摘要

瞬时受体电位阳离子通道亚家族 M 成员 2（TRPM2）参与免疫细胞激活、胰岛素分泌和中枢体温调节。TRPM2 可在结合细胞质 Ca2+和二磷酸腺苷核糖（ADPR）后开启。本文呈现了 （nvTRPM2）在脂纳米盘中与 Ca2+和 ADPR-2'-磷酸结合的 2.5 Å 冷冻电镜结构。与无核苷酸的 nvTRPM2 相比，核苷酸结合诱导的蛋白三个“核心”层的运动可分解为从刺胞动物到人保守的一组刚体旋转。通过对工程化半胱氨酸对进行共价交联，我们系统地将细胞质层固定在特定构象中，并研究其对门控开启/关闭的影响。数据表明，第三层的核苷酸结合破坏了抑制性亚基间相互作用，允许第二层旋转，从而扩展位于第一层的门。被捕获在这种“激活”状态下的通道不再依赖核苷酸，而是通过单独结合 Ca2+打开。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/4761200c7b6f/pnas.2415548121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/371daf4c1d12/pnas.2415548121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/3b03eb4b71ce/pnas.2415548121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/5c81323c17e1/pnas.2415548121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/91280a880cac/pnas.2415548121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/bee21bab959e/pnas.2415548121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/50637107b48f/pnas.2415548121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/6c5281bfe498/pnas.2415548121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/4761200c7b6f/pnas.2415548121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/371daf4c1d12/pnas.2415548121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/3b03eb4b71ce/pnas.2415548121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/5c81323c17e1/pnas.2415548121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/91280a880cac/pnas.2415548121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/bee21bab959e/pnas.2415548121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/50637107b48f/pnas.2415548121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/6c5281bfe498/pnas.2415548121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82bb/11573590/4761200c7b6f/pnas.2415548121fig08.jpg

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本文引用的文献

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Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution.在一种古老的 TRPM 通道酶中偶联酶活性和门控及其分子进化。
Nat Struct Mol Biol. 2024 Oct;31(10):1509-1521. doi: 10.1038/s41594-024-01316-4. Epub 2024 May 21.
2
2'-deoxy-ADPR activates human TRPM2 faster than ADPR and thereby induces higher currents at physiological Ca concentrations.2'-脱氧-ADPR比ADPR更快地激活人类TRPM2，从而在生理钙浓度下诱导出更高的电流。
Front Immunol. 2024 Jan 22;15:1294357. doi: 10.3389/fimmu.2024.1294357. eCollection 2024.
3
TRPM2 - An adjustable thermostat.
TRPM2- 一个可调节的恒温器。
Cell Calcium. 2024 Mar;118:102850. doi: 10.1016/j.ceca.2024.102850. Epub 2024 Jan 11.
4
Protein kinase C-mediated phosphorylation of transient receptor potential melastatin type 2 Thr738 counteracts the effect of cytosolic Ca and elevates the temperature threshold.蛋白激酶 C 介导的瞬时受体电位 melastatin 型 2 Thr738 的磷酸化作用拮抗细胞质 Ca 的作用并提高温度阈值。
J Physiol. 2022 Oct;600(19):4287-4302. doi: 10.1113/JP283350. Epub 2022 Sep 12.
5
A synaptic temperature sensor for body cooling.一种用于身体降温的突触温度传感器。
Neuron. 2021 Oct 20;109(20):3283-3297.e11. doi: 10.1016/j.neuron.2021.10.001.
6
TRPM2 ion channels steer neutrophils towards a source of hydrogen peroxide.TRPM2 离子通道引导中性粒细胞向过氧化氢源移动。
Sci Rep. 2021 Apr 29;11(1):9339. doi: 10.1038/s41598-021-88224-5.
7
Selective profiling of N- and C-terminal nucleotide-binding sites in a TRPM2 channel.选择性分析 TRPM2 通道的 N 端和 C 端核苷酸结合位点。
J Gen Physiol. 2020 May 4;152(5). doi: 10.1085/jgp.201912533.
8
The Sensory Coding of Warm Perception.温暖感知的感觉编码。
Neuron. 2020 Jun 3;106(5):830-841.e3. doi: 10.1016/j.neuron.2020.02.035. Epub 2020 Mar 23.
9
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Elife. 2019 Sep 12;8:e50175. doi: 10.7554/eLife.50175.
10
Enzyme activity and selectivity filter stability of ancient TRPM2 channels were simultaneously lost in early vertebrates.古生代 TRPM2 通道的酶活性和选择性滤器稳定性在早期脊椎动物中同时丧失。
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