Department of Biological Sciences, Vanderbilt University, Nashville, TN, U.S.A.
Center for Structural Biology, Vanderbilt University, Nashville, TN, U.S.A.
Biochem Soc Trans. 2020 Oct 30;48(5):2261-2272. doi: 10.1042/BST20200552.
Retromer (VPS26/VPS35/VPS29) is a highly conserved eukaryotic protein complex that localizes to endosomes to sort transmembrane protein cargoes into vesicles and elongated tubules. Retromer mediates retrieval pathways from endosomes to the trans-Golgi network in all eukaryotes and further facilitates recycling pathways to the plasma membrane in metazoans. In cells, retromer engages multiple partners to orchestrate the formation of tubulovesicular structures, including sorting nexin (SNX) proteins, cargo adaptors, GTPases, regulators, and actin remodeling proteins. Retromer-mediated pathways are especially important for sorting cargoes required for neuronal maintenance, which links retromer loss or mutations to multiple human brain diseases and disorders. Structural and biochemical studies have long contributed to the understanding of retromer biology, but recent advances in cryo-electron microscopy and cryo-electron tomography have further uncovered exciting new snapshots of reconstituted retromer structures. These new structures reveal retromer assembles into an arch-shaped scaffold and suggest the scaffold may be flexible and adaptable in cells. Interactions with cargo adaptors, particularly SNXs, likely orient the scaffold with respect to phosphatidylinositol-3-phosphate (PtdIns3P)-enriched membranes. Pharmacological small molecule chaperones have further been shown to stabilize retromer in cultured cell and mouse models, but mechanisms by which these molecules bind remain unknown. This review will emphasize recent structural and biophysical advances in understanding retromer structure as the field moves towards a molecular view of retromer assembly and regulation on membranes.
Retromer (VPS26/VPS35/VPS29) 是一种高度保守的真核蛋白复合物，定位于内体，将跨膜蛋白货物分拣到小泡和长管状结构中。Retromer 在所有真核生物中介导从内体到高尔基体反式网络的回收途径，并进一步促进后生动物到质膜的再循环途径。在细胞中，Retromer 与多个伙伴结合，协调管状囊泡结构的形成，包括分选连接蛋白（SNX）蛋白、货物衔接器、GTPases、调节剂和肌动蛋白重塑蛋白。Retromer 介导的途径对于分拣神经元维持所需的货物尤其重要，这将 Retromer 的缺失或突变与多种人类大脑疾病和紊乱联系起来。结构和生化研究长期以来一直有助于了解 Retromer 生物学，但最近的低温电子显微镜和低温电子断层扫描技术的进展进一步揭示了重新构成的 Retromer 结构令人兴奋的新快照。这些新结构表明，Retromer 组装成一个拱形支架，并表明支架在细胞中可能是灵活和适应性的。与货物衔接器（特别是 SNX）的相互作用可能会使支架相对于富含磷脂酰肌醇-3-磷酸（PtdIns3P）的膜定向。已进一步表明，药理学小分子伴侣在培养细胞和小鼠模型中稳定 Retromer，但这些分子结合的机制仍不清楚。本综述将强调最近在理解 Retromer 结构方面的结构和生物物理进展，因为该领域朝着在膜上组装和调节 Retromer 的分子观点发展。
