AI-driven mechanistic analysis of conformational dynamics in CNNM/CorC Mg2+ transporters

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-11-06 DOI:10.1016/j.str.2024.10.021

Jie Ma, Xingyu Song, Yosuke Funato, Xinyu Teng, Yichen Huang, Hiroaki Miki, Wenning Wang, Motoyuki Hattori

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Abstract

The CNNM/CorC Mg²⁺ transporters are widely conserved in eukaryotes (cyclin M [CNNM]) and prokaryotes (CorC) and participate in various biological processes. Previous structural analyses of the CorC transmembrane domain in the Mg²⁺-bound inward-facing conformation revealed the conserved Mg²⁺ recognition mechanism in the CNNM/CorC family; however, the conformational dynamics in the Mg²⁺ transport cycle remain unclear because structures in other conformations are unknown. Here, we used AlphaFold structure prediction to predict the occluded-like and outward-facing-like conformations of the CorC and CNNM proteins and identified conserved hydrophilic interactions close to the cytoplasmic side in these conformations. Molecular dynamics simulations and biochemical cross-linking showed that these conserved hydrophilic interactions are stable, especially in the outward-facing-like conformation. Furthermore, mutational analysis revealed that the residues involved in these hydrophilic interactions on the cytoplasmic side are important for Mg²⁺ transport in the CorC and CNNM proteins. Our work provides mechanistic insights into the transport cycle of the CNNM/CorC family.

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人工智能驱动的 CNNM/CorC Mg2+ 转运体构象动力学机理分析

CNNM/CorC Mg2+ 转运体在真核生物（细胞周期蛋白 M [CNNM]）和原核生物（CorC）中广泛保守，参与各种生物过程。之前对处于 Mg2+ 结合内向构象的 CorC 跨膜结构域进行的结构分析揭示了 CNNM/CorC 家族中保守的 Mg2+ 识别机制；然而，由于其他构象的结构未知，Mg2+ 转运循环中的构象动态仍不清楚。在此，我们利用 AlphaFold 结构预测法预测了 CorC 和 CNNM 蛋白的闭锁样构象和外向样构象，并确定了这些构象中靠近细胞质侧的保守亲水相互作用。分子动力学模拟和生化交联表明，这些保守的亲水相互作用是稳定的，尤其是在向外型构象中。此外，突变分析表明，参与细胞质侧这些亲水相互作用的残基对 CorC 和 CNNM 蛋白的 Mg2+ 运输非常重要。我们的研究为 CNNM/CorC 家族的转运循环提供了机制上的启示。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.