Tuli Farzana, Kane Patricia M
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, United States.
Front Mol Biosci. 2023 Jun 16;10:1168680. doi: 10.3389/fmolb.2023.1168680. eCollection 2023.
Vacuolar H-ATPases (V-ATPases) acidify several organelles in all eukaryotic cells and export protons across the plasma membrane in a subset of cell types. V-ATPases are multisubunit enzymes consisting of a peripheral subcomplex, V, that is exposed to the cytosol and an integral membrane subcomplex, V, that contains the proton pore. The V a-subunit is the largest membrane subunit and consists of two domains. The N-terminal domain of the a-subunit (aNT) interacts with several V and V subunits and serves to bridge the V and V subcomplexes, while the C-terminal domain contains eight transmembrane helices, two of which are directly involved in proton transport. Although there can be multiple isoforms of several V-ATPase subunits, the a-subunit is encoded by the largest number of isoforms in most organisms. For example, the human genome encodes four a-subunit isoforms that exhibit a tissue- and organelle-specific distribution. In the yeast S. , the two a-subunit isoforms, Golgi-enriched Stv1 and vacuolar Vph1, are the only V-ATPase subunit isoforms. Current structural information indicates that a-subunit isoforms adopt a similar backbone structure but sequence variations allow for specific interactions during trafficking and in response to cellular signals. V-ATPases are subject to several types of environmental regulation that serve to tune their activity to their cellular location and environmental demands. The position of the aNT domain in the complex makes it an ideal target for modulating V-V interactions and regulating enzyme activity. The yeast a-subunit isoforms have served as a paradigm for dissecting interactions of regulatory inputs with subunit isoforms. Importantly, structures of yeast V-ATPases containing each a-subunit isoform are available. Chimeric a-subunits combining elements of Stv1NT and Vph1NT have provided insights into how regulatory inputs can be integrated to allow V-ATPases to support cell growth under different stress conditions. Although the function and distribution of the four mammalian a-subunit isoforms present additional complexity, it is clear that the aNT domains of these isoforms are also subject to multiple regulatory interactions. Regulatory mechanisms that target mammalian a-subunit isoforms, and specifically the aNT domains, will be described. Altered V-ATPase function is associated with multiple diseases in humans. The possibility of regulating V-ATPase subpopulations via their isoform-specific regulatory interactions are discussed.
液泡型H⁺-ATP酶（V-ATP酶）可酸化所有真核细胞中的多种细胞器，并在部分细胞类型中跨质膜输出质子。V-ATP酶是多亚基酶，由暴露于胞质溶胶的外周亚复合体V和包含质子孔的整合膜亚复合体V组成。V a亚基是最大的膜亚基，由两个结构域组成。a亚基的N端结构域（aNT）与多个V和V亚基相互作用，用于连接V和V亚复合体，而C端结构域包含八个跨膜螺旋，其中两个直接参与质子运输。尽管几种V-ATP酶亚基可能存在多种同工型，但在大多数生物体中，a亚基由数量最多的同工型编码。例如，人类基因组编码四种a亚基同工型，它们表现出组织和细胞器特异性分布。在酿酒酵母中，两种a亚基同工型，即高尔基体富集的Stv1和液泡型Vph1，是仅有的V-ATP酶亚基同工型。目前的结构信息表明，a亚基同工型采用相似的主链结构，但序列变异允许在运输过程中以及对细胞信号作出反应时进行特异性相互作用。V-ATP酶受到多种类型的环境调节，这些调节可根据其细胞定位和环境需求来调整其活性。aNT结构域在复合体中的位置使其成为调节V-V相互作用和调节酶活性的理想靶点。酵母a亚基同工型已成为剖析调节输入与亚基同工型相互作用的范例。重要的是，含有每种a亚基同工型的酵母V-ATP酶的结构是可用的。结合Stv1NT和Vph1NT元件的嵌合a亚基，为深入了解如何整合调节输入以使V-ATP酶在不同应激条件下支持细胞生长提供了线索。尽管四种哺乳动物a亚基同工型的功能和分布增加了复杂性，但很明显这些同工型的aNT结构域也受到多种调节相互作用的影响。将描述针对哺乳动物a亚基同工型，特别是aNT结构域的调节机制。V-ATP酶功能改变与人类多种疾病相关。讨论了通过其同工型特异性调节相互作用来调节V-ATP酶亚群的可能性。
