Wilson Christian A M, Alfaro-Valdés Hilda M, Kaplan Merve, D'Alessio Cecilia
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Faculty of Science, Universidad de Valparaíso, Valparaíso, Chile.
Biophys Rev. 2025 Apr 7;17(2):435-447. doi: 10.1007/s12551-025-01313-x. eCollection 2025 Apr.
About one-third of the proteins synthesized in eukaryotic cells are directed to the secretory pathway, where close to 70% are being -glycosylated. -glycosylation is a crucial modification for various cellular processes, including endoplasmic reticulum (ER) glycoprotein folding quality control, lysosome delivery, and cell signaling. The defects in glycosylation can lead to severe developmental diseases. For the proteins to be glycosylated, they must be translocated to the ER through the Sec61 translocon channel, either via co-translationally or post-translationally. glycosylation not only could accelerate post-translational translocation but may also enhance protein stability, while protein folding can assist in their movement into the ER. However, the precise mechanisms by which glycosylation and folding influence translocation remain poorly understood. The chaperone BiP is essential for post-translational translocation, using a "ratchet" mechanism to facilitate protein entry into the ER. Although research has explored how BiP interacts with protein substrates, there has been less focus on its binding to glycosylated substrates. Here, we review the effect of glycosylation on protein translocation, employing single-molecule studies and ensembles approaches to clarify the roles of BiP and glycosylation in these processes. Our review explores the possibility of a direct relationship between translocation and a ratchet effect of glycosylation and the importance of BiP in binding glycosylated proteins for the ER quality control system.
The online version contains supplementary material available at 10.1007/s12551-025-01313-x.
在真核细胞中合成的蛋白质约有三分之一被导向分泌途径，其中近70%会进行N-糖基化修饰。N-糖基化修饰对于各种细胞过程至关重要，包括内质网（ER）糖蛋白折叠质量控制、溶酶体转运和细胞信号传导。糖基化缺陷可导致严重的发育性疾病。对于要进行糖基化修饰的蛋白质，它们必须通过Sec61转运通道共翻译或翻译后转运至内质网。N-糖基化不仅可以加速翻译后转运，还可能增强蛋白质稳定性，而蛋白质折叠有助于其进入内质网。然而，糖基化和折叠影响转运的精确机制仍知之甚少。伴侣蛋白BiP对于翻译后转运至关重要，它利用“棘轮”机制促进蛋白质进入内质网。尽管已有研究探讨了BiP如何与蛋白质底物相互作用，但较少关注其与糖基化底物的结合。在这里，我们回顾了糖基化对蛋白质转运的影响，采用单分子研究和整体方法来阐明BiP和糖基化在这些过程中的作用。我们的综述探讨了转运与糖基化棘轮效应之间直接关系的可能性，以及BiP在结合糖基化蛋白以维持内质网质量控制系统中的重要性。
在线版本包含可在10.1007/s12551-025-01313-x获取的补充材料。
