Wang Xiaojie, Bai Zhongjian, Wallis Ciara, Wang Huanchen, Han Yaoyao, Jin Ruitao, Lei Mingguang, Yang Tian, Gu Chunfang, Jessen Henning, Shears Stephen, Sun Yadong, Corry Ben, Zhang Yixiao
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China.
Research School of Biology, Australian National University, Arts and Culture Trust, Acton 2601, Australia.
Mol Cell. 2025 Aug 19. doi: 10.1016/j.molcel.2025.08.003.
XPR1 is emerging as the only known inorganic phosphate (Pi) exporter in humans, critical for Pi homeostasis, with its activity stimulated by inositol pyrophosphate InsP8 and regulated by neuronal scaffold protein KIDINS220. Our structural studies reveal that InsP8 specifically activates XPR1 in a stepwise manner, involving profound SYG1/PHO/XPR1 (SPX) domain movements. Each XPR1 subunit functions with four gating states, in which Pi permeates a constriction site via a "knock-kiss-kick" process. By contrast, KIDINS220 delicately stabilizes XPR1 in a closed conformation through multiple mechanisms, one of which involves trapping the XPR1 α1 helix-critical for InsP8 binding-within an interaction hub. InsP8 serves as a key to release KIDINS220's restraint, reinforcing a "key-to-locks" mechanism to safeguard the stepwise activation. Additionally, our study provides direct structural insights into XPR1-associated neuronal disorders and highlights the evolutionary conservation and divergence among XPR1 orthologs, offering a comprehensive understanding of Pi homeostasis across species.
XPR1正逐渐成为人类已知的唯一无机磷酸盐（Pi）转运体，对Pi稳态至关重要，其活性受肌醇焦磷酸InsP8刺激，并受神经元支架蛋白KIDINS220调控。我们的结构研究表明，InsP8以逐步方式特异性激活XPR1，这涉及SYG1/PHO/XPR1（SPX）结构域的显著移动。每个XPR1亚基通过四种门控状态发挥作用，其中Pi通过“敲-吻-踢”过程穿过一个收缩位点。相比之下，KIDINS220通过多种机制精细地将XPR1稳定在封闭构象，其中一种机制涉及将对InsP8结合至关重要的XPR1 α1螺旋捕获在一个相互作用中心内。InsP8作为释放KIDINS220抑制作用的钥匙，强化了一种“钥匙-锁”机制以保障逐步激活。此外，我们的研究为与XPR1相关的神经元疾病提供了直接的结构见解，并突出了XPR1直系同源物之间的进化保守性和差异性，从而全面理解跨物种的Pi稳态。
