小柯机器人

荷兰格罗宁根大学Cristina Paulino团队揭示由电压和cAMP触发的精子特异性溶质载体结构。这一研究成果于2023年10月25日在线发表在国际学术期刊《自然》上。

研究人员对海胆SpSLC9C1在没有配体和有配体的情况下的结构进行了研究，并揭示了其整体结构域排列和新的结构耦合元件。通过这些结构，研究人员提出了一个门控模型，即电压传感器的运动通过新表征的耦合螺旋传递的长距离异位效应，间接导致交换单元从锁定状态释放。研究人员进一步提出，其配体环磷酸腺苷（cyclic AMP）的调节作用是通过破坏细胞膜二聚体界面来实现的，从而降低了电压感应结构域中S4运动的能量障碍。由于SLC9C1成员已被证明对男性生育力至关重要，包括在哺乳动物中，因此这个结构代表了开发新型按需避孕药物的潜在新平台。

据悉，新鉴定的精子特异性Na⁺/H⁺交换蛋白因其独特的三方结构域组成而脱颖而出。它将一个经典的溶质载体单元与离子通道中常见的调控结构域（即电压感应结构域和环核苷酸结合结构域）结合在一起，这使它成为一个机械嵌合体和一个严格由膜电压激活的二级活性转运体。

附：英文原文

Title: Structures of a sperm-specific solute carrier gated by voltage and cAMP

Author: Kalienkova, Valeria, Peter, Martin F., Rheinberger, Jan, Paulino, Cristina

Issue&Volume: 2023-10-25

Abstract: The newly characterized sperm-specific Na+/H+ exchanger stands out by its unique tripartite domain composition1,2. It unites a classical solute carrier unit with regulatory domains usually found in ion channels, namely, a voltage-sensing domain and a cyclic-nucleotide binding domain1,3, which makes it a mechanistic chimera and a secondary-active transporter activated strictly by membrane voltage. Our structures of the sea urchin SpSLC9C1 in the absence and presence of ligands reveal the overall domain arrangement and new structural coupling elements. They allow us to propose a gating model, where movements in the voltage sensor indirectly cause the release of the exchanging unit from a locked state through long-distance allosteric effects transmitted by the newly characterized coupling helices. We further propose that modulation by its ligand cyclic AMP occurs by means of disruption of the cytosolic dimer interface, which lowers the energy barrier for S4 movements in the voltage-sensing domain. As SLC9C1 members have been shown to be essential for male fertility, including in mammals2,4,5, our structure represents a potential new platform for the development of new on-demand contraceptives.

DOI: 10.1038/s41586-023-06629-w

Source: https://www.nature.com/articles/s41586-023-06629-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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