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高分辨率蛋白质组学鉴定的天然 TRPM7 通道复合物的分子外观。

The molecular appearance of native TRPM7 channel complexes identified by high-resolution proteomics.

机构信息

Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.

出版信息

Elife. 2021 Nov 12;10:e68544. doi: 10.7554/eLife.68544.

DOI:10.7554/eLife.68544
PMID:34766907
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8616561/
Abstract

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed membrane protein consisting of ion channel and protein kinase domains. TRPM7 plays a fundamental role in the cellular uptake of divalent cations such as Zn, Mg, and Ca, and thus shapes cellular excitability, plasticity, and metabolic activity. The molecular appearance and operation of TRPM7 channels in native tissues have remained unresolved. Here, we investigated the subunit composition of endogenous TRPM7 channels in rodent brain by multi-epitope affinity purification and high-resolution quantitative mass spectrometry (MS) analysis. We found that native TRPM7 channels are high-molecular-weight multi-protein complexes that contain the putative metal transporter proteins CNNM1-4 and a small G-protein ADP-ribosylation factor-like protein 15 (ARL15). Heterologous reconstitution experiments confirmed the formation of TRPM7/CNNM/ARL15 ternary complexes and indicated that complex formation effectively and specifically impacts TRPM7 activity. These results open up new avenues towards a mechanistic understanding of the cellular regulation and function of TRPM7 channels.

摘要

瞬时受体电位 melastatin 亚家族成员 7（TRPM7）是一种广泛表达的膜蛋白，由离子通道和蛋白激酶结构域组成。TRPM7 在二价阳离子（如 Zn、Mg 和 Ca）的细胞摄取中发挥着基本作用，从而影响细胞的兴奋性、可塑性和代谢活性。天然组织中 TRPM7 通道的分子外观和功能仍未得到解决。在这里，我们通过多表位亲和纯化和高分辨率定量质谱（MS）分析研究了啮齿动物大脑中内源性 TRPM7 通道的亚基组成。我们发现，天然 TRPM7 通道是高分子量多蛋白复合物，包含假定的金属转运蛋白 CNNM1-4 和小 G 蛋白 ADP-核糖基化因子样蛋白 15（ARL15）。异源重组实验证实了 TRPM7/CNNM/ARL15 三元复合物的形成，并表明复合物的形成可有效且特异性地影响 TRPM7 活性。这些结果为深入了解 TRPM7 通道的细胞调节和功能提供了新的途径。

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