Structure-Based Function and Regulation of NCX Variants: Updates and Challenges.
Structure-Based Function and Regulation of NCX Variants: Updates and Challenges.
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DOI：
10.3390/ijms24010061
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发表时间：
2022-12-21
影响因子：
5.6
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中科院分区：
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在从细菌到人类的各种生物系统中，质膜稳态Na+/Ca~(2+)交换器(NCX)介导Ca~(2+)排出/进入，从而动态地形成Ca~(2+)信号。NCX基因的同源异构体及其剪接变异体以组织特异性的方式表达，并在运输速率和调控特异性方面显示出近104倍的差异，以满足细胞的特定要求。NCX突变体的选择性药理学靶向可能使许多临床应用受益，尽管这种干预仍然具有挑战性，主要是因为无法获得真核细胞NCX的完整结构。古生菌NCX_Mj的晶体结构与生物物理、计算和功能分析相结合，为解决离子传输机制提供了突破。然而，NCX_Mj(其大小几乎是哺乳动物NCX的三倍)不能作为一个结构动力学模型来模拟真核生物NCX所具有的高转运速率和调控模块。分离的调控结构域(从真核生物NCX获得)的晶体结构及其生物物理分析的SAXS，核磁共振，FRET，和HDX-MS方法揭示了调控模块的结构差异。尽管取得了这些成就，但目前仍不清楚多结构域相互作用如何解码和整合不同的变构信号，从而在给定的同源异构体/剪接变异体中产生不同的调控结果。本文从未来发展的角度对相关问题进行了总结。
The plasma-membrane homeostasis Na+/Ca2+ exchangers (NCXs) mediate Ca2+ extrusion/entry to dynamically shape Ca2+ signaling/in biological systems ranging from bacteria to humans. The NCX gene orthologs, isoforms, and their splice variants are expressed in a tissue-specific manner and exhibit nearly 104-fold differences in the transport rates and regulatory specificities to match the cell-specific requirements. Selective pharmacological targeting of NCX variants could benefit many clinical applications, although this intervention remains challenging, mainly because a full-size structure of eukaryotic NCX is unavailable. The crystal structure of the archaeal NCX_Mj, in conjunction with biophysical, computational, and functional analyses, provided a breakthrough in resolving the ion transport mechanisms. However, NCX_Mj (whose size is nearly three times smaller than that of mammalian NCXs) cannot serve as a structure-dynamic model for imitating high transport rates and regulatory modules possessed by eukaryotic NCXs. The crystal structures of isolated regulatory domains (obtained from eukaryotic NCXs) and their biophysical analyses by SAXS, NMR, FRET, and HDX-MS approaches revealed structure-based variances of regulatory modules. Despite these achievements, it remains unclear how multi-domain interactions can decode and integrate diverse allosteric signals, thereby yielding distinct regulatory outcomes in a given ortholog/isoform/splice variant. This article summarizes the relevant issues from the perspective of future developments.
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