Hendus-Altenburger Ruth, Kragelund Birthe B, Pedersen Stine Falsig
Section for Biomolecular Sciences, Department of Biology, University of Copenhagen, Copenhagen, Denmark; Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Section for Biomolecular Sciences, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Curr Top Membr. 2014;73:69-148. doi: 10.1016/B978-0-12-800223-0.00002-5.
Mammalian Na⁺/H⁺ exchangers of the SLC9A family are widely expressed and involved in numerous essential physiological processes. Their primary function is to mediate the 1:1 exchange of Na⁺ for H⁺ across the membrane in which they reside, and they play central roles in regulation of body, cellular, and organellar pH. Their function is tightly regulated through mechanisms involving interactions with multiple protein and lipid-binding partners, phosphorylations, and other posttranslational modifications. Biochemical and mutational analyses indicate that the SLC9As have a short intracellular N-terminus, 12 transmembrane (TM) helices necessary and sufficient for ion transport, and a C-terminal cytoplasmic tail region with essential regulatory roles. No high-resolution structures of the SLC9As exist; however, models based on crystal structures of the bacterial NhaAs support the 12 TM organization and suggest that TMIV and XI may form a central part of the ion-translocation pathway, whereas pH sensing may involve TMII, TMIX, and several intracellular loops. Similar to most ion transporters studied, SLC9As likely exist as coupled dimers in the membrane, and this appears to be important for the well-studied cooperativity of H⁺ binding. The aim of this work is to summarize and critically discuss the currently available evidence on the structural dynamics, regulation, and binding partner interactions of SLC9As, focusing in particular on the most widely studied isoform, SLC9A1/NHE1. Further, novel bioinformatic and structural analyses are provided that to some extent challenge the existing paradigm on how ions are transported by mammalian SLC9As.
SLC9A 家族的哺乳动物 Na⁺/H⁺ 交换体广泛表达，并参与众多重要的生理过程。它们的主要功能是介导 Na⁺ 与 H⁺ 在其所在膜上进行 1:1 的交换，在调节机体、细胞和细胞器的 pH 方面发挥核心作用。它们的功能通过多种机制受到严格调控，这些机制包括与多种蛋白质和脂质结合伴侣的相互作用、磷酸化以及其他翻译后修饰。生化和突变分析表明，SLC9As 具有一个短的细胞内 N 端、12 个对离子转运必要且充分的跨膜（TM）螺旋，以及一个具有重要调节作用的 C 端胞质尾部区域。目前不存在 SLC9As 的高分辨率结构；然而，基于细菌 NhaAs 晶体结构的模型支持 12 个 TM 的结构组织，并表明 TMIV 和 XI 可能构成离子转运途径的核心部分，而 pH 传感可能涉及 TMII、TMIX 和几个细胞内环。与大多数研究的离子转运体类似，SLC9As 可能以偶联二聚体的形式存在于膜中，这似乎对已充分研究的 H⁺ 结合协同性很重要。这项工作的目的是总结并批判性地讨论目前关于 SLC9As 的结构动力学、调节以及结合伴侣相互作用的现有证据，特别关注研究最广泛的异构体 SLC9A1/NHE1。此外，还提供了新的生物信息学和结构分析，在一定程度上挑战了关于哺乳动物 SLC9As 如何转运离子的现有范式。
