Ostα/β的结构揭示了独特的折叠和胆汁酸转运机制，这一成果由上海交通大学医学院附属瑞金医院医药结构生物转化中心徐华强教授与上海交通大学医学院附属仁济医院马雄教授团队合作揭示。2026年1月28日出版的《自然》杂志发表了这一最新研究成果。

本研究通过冷冻电镜解析了人源Ostα/β在非结合状态与底物结合状态下的结构（分辨率2.6–3.1 Å），揭示了一种独特的膜蛋白结构，定义了一种新的转运蛋白类。Ostα/β形成一个对称的四聚体异二聚体，每个Ostα亚基显示一个新的七跨膜折叠，由一个单一的Ostβ跨膜螺旋增强。这种结构通过广泛的脂质修饰来稳定，包括一个棕榈酰化的富含半胱氨酸的基基，形成一个横向底物结合槽。这些结构揭示了一种独特的转运途径，其特征是两个底物结合位点由两路螺旋门控通道连接。这种设计在进化相关的TMEM184家族中保守，表明一种古老的底物易位机制。电生理研究证实了由电化学梯度驱动的电压敏感的双向传输，阐明了Ostα/β在体内的外流作用。脂质相互作用，特别是棕榈酰化依赖性运输，对稳定性和功能至关重要。这些发现阐明了Ostα/β的分子机制，为疾病相关突变提供了结构基础，并建立了脂质修饰膜运输的范式。

据悉，胆汁酸和类固醇激素的体内平衡对人体健康至关重要，其破坏与代谢和内分泌紊乱有关。有机溶质转运体Ostα/β是肠肝循环中胆汁酸外排所必需的，但其机制一直没有得到阐明。

附：英文原文

Title: Structures of Ostα/β reveal a unique fold and bile acid transport mechanism

Author: Yang, Xuemei, Cui, Nana, Li, Tianyu, He, Xinheng, Zhang, Heng, Wu, Canrong, Li, Yang, Ma, Xiong, Xu, H. Eric

Issue&Volume: 2026-01-28

Abstract: Bile acid and steroid hormone homeostasis are critical for human health, with disruptions linked to metabolic and endocrine disorders1,2. The organic solute transporter Ostα/β, essential for bile acid efflux in enterohepatic circulation3, has long defied mechanistic elucidation. Here we present cryogenic electron microscopy structures of human Ostα/β in apo and substrate-bound states at 2.6–3.1 resolution, revealing a distinctive membrane protein architecture that defines a new transporter class. Ostα/β forms a symmetric tetramer of heterodimers, with each Ostα subunit showing a new seven-transmembrane fold, augmented by a single transmembrane helix of Ostβ. This architecture is stabilized by extensive lipid modifications, including a palmitoylated cysteine-rich motif that forms a lateral substrate-binding groove. The structures uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit. This design, conserved in the evolutionarily related TMEM184 family, suggests an ancient mechanism for substrate translocation. Electrophysiological studies demonstrate voltage-sensitive, bidirectional transport driven by electrochemical gradients, elucidating the efflux role of Ostα/β in vivo. Lipid interactions, notably palmitoylation-dependent trafficking, emerge as critical for stability and function. These findings clarify the molecular mechanism of Ostα/β, provide a structural basis for disease-associated mutations4,5 and establish a paradigm for lipid-modified membrane transport.

DOI: 10.1038/s41586-025-10029-7

Source: https://www.nature.com/articles/s41586-025-10029-7