Departments of Pediatrics and Physiology & Biophysics, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, USA.
Instituto de Histología y Embriología de Mendoza (IHEM/CONICET-UNCuyo), School of Medicine, National University of Cuyo, Mendoza, CP, Argentina.
Nat Commun. 2021 Jun 22;12(1):3855. doi: 10.1038/s41467-021-24145-1.
Human voltage-gated proton channels (hHv1) extrude protons from cells to compensate for charge and osmotic imbalances due metabolism, normalizing intracellular pH and regulating protein function. Human albumin (Alb), present at various levels throughout the body, regulates oncotic pressure and transports ligands. Here, we report Alb is required to activate hHv1 in sperm and neutrophils. Dose-response studies reveal the concentration of Alb in semen is too low to activate hHv1 in sperm whereas the higher level in uterine fluid yields proton efflux, allowing capacitation, the acrosomal reaction, and oocyte fertilization. Likewise, Alb activation of hHv1 in neutrophils is required to sustain production and release of reactive oxygen species during the immune respiratory burst. One Alb binds to both voltage sensor domains (VSDs) in hHv1, enhancing open probability and increasing proton current. A computational model of the Alb-hHv1 complex, validated by experiments, identifies two sites in Alb domain II that interact with the VSDs, suggesting an electrostatic gating modification mechanism favoring the active "up" sensor conformation. This report shows how sperm are triggered to fertilize, resolving how hHv1 opens at negative membrane potentials in sperm, and describes a role for Alb in physiology that will operate in the many tissues expressing hHv1.
人电压门控质子通道（hHv1）将质子从细胞中排出，以补偿代谢引起的电荷和渗透失衡，使细胞内 pH 值恢复正常，并调节蛋白质功能。人白蛋白（Alb）存在于全身各个部位，调节渗透压并转运配体。在这里，我们报告 Alb 是激活精子和中性粒细胞中 hHv1 所必需的。剂量反应研究表明，精液中 Alb 的浓度太低，无法激活精子中的 hHv1，而子宫液中的 Alb 浓度较高则会产生质子外流，从而允许顶体反应和卵母细胞受精。同样，中性粒细胞中 Alb 激活 hHv1 对于维持免疫呼吸爆发期间活性氧物质的产生和释放是必需的。一个 Alb 结合到 hHv1 的两个电压传感器结构域（VSD）上，从而增加开放概率并增加质子电流。通过实验验证的 Alb-hHv1 复合物的计算模型确定了 Alb 结构域 II 中的两个与 VSD 相互作用的位点，这表明存在一种静电门控修饰机制，有利于激活的“向上”传感器构象。本报告展示了精子如何被触发受精，解决了 hHv1 如何在精子中在负膜电位下打开的问题，并描述了 Alb 在表达 hHv1 的许多组织中发挥作用的生理作用。
