Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
Department of Chemistry, University of Oxford, Oxford, UK.
EMBO J. 2020 Dec 15;39(24):e105908. doi: 10.15252/embj.2020105908. Epub 2020 Oct 29.
Na /H exchangers (NHEs) are ancient membrane-bound nanomachines that work to regulate intracellular pH, sodium levels and cell volume. NHE activities contribute to the control of the cell cycle, cell proliferation, cell migration and vesicle trafficking. NHE dysfunction has been linked to many diseases, and they are targets of pharmaceutical drugs. Despite their fundamental importance to cell homeostasis and human physiology, structural information for the mammalian NHE was lacking. Here, we report the cryogenic electron microscopy structure of NHE isoform 9 (SLC9A9) from Equus caballus at 3.2 Å resolution, an endosomal isoform highly expressed in the brain and associated with autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Despite low sequence identity, the NHE9 architecture and ion-binding site are remarkably similar to distantly related bacterial Na /H antiporters with 13 transmembrane segments. Collectively, we reveal the conserved architecture of the NHE ion-binding site, their elevator-like structural transitions, the functional implications of autism disease mutations and the role of phosphoinositide lipids to promote homodimerization that, together, have important physiological ramifications.
钠/氢交换器（NHEs）是古老的膜结合纳米机器，可调节细胞内 pH 值、钠离子水平和细胞体积。NHE 活性有助于控制细胞周期、细胞增殖、细胞迁移和囊泡运输。NHE 功能障碍与许多疾病有关，它们是药物的靶点。尽管它们对细胞内稳态和人体生理学至关重要，但哺乳动物 NHE 的结构信息仍然缺乏。在这里，我们报告了马属 NHE 同工型 9（SLC9A9）在 3.2 Å 分辨率下的冷冻电子显微镜结构，这是一种内体同工型，在大脑中高度表达，与自闭症谱系（ASD）和注意力缺陷多动障碍（ADHD）有关。尽管序列同一性较低，但 NHE9 的结构和离子结合位点与远缘细菌的 Na /H 反向转运蛋白非常相似，后者具有 13 个跨膜片段。总的来说，我们揭示了 NHE 离子结合位点的保守结构、它们的电梯样结构转换、自闭症疾病突变的功能意义以及磷酸肌醇脂质促进同源二聚化的作用，这些共同具有重要的生理意义。
