1)中国科学院合肥物质科学研究院强磁场科学中心,合肥 230031;2)中国科学技术大学苏州高等研究院生物医学工程学院,苏州 215123;3)中国科学技术大学生命科学与医学部,合肥 230026;4)安徽大学生命科学与医学工程学院,合肥 230601;5)上海交通大学张江高等研究院,上海 201203
国家重点研发计划(2022YFC3400500) 和中国科学院合肥大科学中心协同创新培育基金(2022HSC-CIP011) 资助项目。
1)High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China;2)School of Biomedical Engineering, Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou 215123, China;3)Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China;4)School of Life Sciences and Medical Engineering, Anhui University, Hefei 230601, China;5)Zhangjiang Institute for Advanced Studies, Shanghai Jiao Tong University, Shanghai 201203, China
This work was supported by grants from the National Key R&D Program of China (2022YFC3400500) and Collaborative Innovation Program of Hefei Science Center, CAS (2022HSC-CIP011).
糖基化是一种关键的翻译中和翻译后修饰,通过共价键将糖分子连接到蛋白质、脂质或小RNA上,形式高度复杂且多样。蛋白质糖基化是最普遍的修饰之一,参与调控蛋白质功能。G蛋白偶联受体(GPCR)作为人体最大的膜蛋白家族,几乎调控所有生理及病理过程,因而也是目前药物研发中占比最高的靶点类别。绝大多数哺乳动物GPCR会发生糖基化修饰,并深度参与其多个生物学环节:内质网中的折叠与质量控制、向细胞膜的转运与定位、内吞及降解/再循环、配体结合与信号转导、偏向性信号传导,以及受体二聚化。其中既有正向调控,也有负向调控。近年来,单颗粒冷冻电镜(cryo-EM)与X射线晶体学等结构生物学技术的飞跃,正在重塑对GPCR糖基化的认知。如今,高分辨结构揭示了糖链如何从原子层面影响受体的药理学特性。本综述聚焦GPCR超家族中的糖基化现象,系统梳理其对受体功能的影响与调控机制,并评述结构生物学领域的最新进展及未来发展方向。
Glycosylation constitutes a critical, highly intricate, and diverse co- and post-translational modification characterized by the covalent attachment of sugar moieties to proteins, lipids, or small RNAs. Complex glycans are ubiquitously present across nearly all living organisms. Despite their prevalence, our comprehension of glycan diversity remains limited, likely due to the inherent challenges associated with elucidating their structural complexity. Among post-translational modifications, protein glycosylation is notably prevalent, involving the enzymatic transfer of oligosaccharides to specific amino acid residues by glycosyltransferases. This modification plays a pivotal role in modulating protein function, including participation in various biological and biochemical recognition processes. G protein-coupled receptors (GPCRs), encoded by approximately one thousand genes, share a conserved architecture comprising seven transmembrane helices interconnected by three intracellular and three extracellular loops. Representing the largest family of human membrane proteins, GPCRs regulate a vast array of physiological and pathological processes, thereby constituting the most extensive class of therapeutic targets. In mammalian systems, the majority of GPCRs undergo glycosylation predominantly at their extracellular N-terminus or extracellular loops, primarily through N-linked and O-linked glycosylation. These covalent carbohydrate modifications exert profound effects on multiple facets of GPCR biology, including endoplasmic reticulum folding and quality control, membrane trafficking and surface expression, receptor internalization and recycling or degradation, ligand binding and signal transduction, biased signaling, and receptor dimerization. Notably, glycosylation can exert both positive and negative regulatory influences on these processes. Dysregulation of GPCR glycosylation has been implicated in a range of pathological conditions, such as cancer, diabetes, and neurological disorders, underscoring its physiological and pathological significance. Aberrant glycosylation patterns may lead to dysfunctional receptor signaling, thereby contributing to disease progression. Consequently, elucidating the precise roles of glycosylation in GPCR function not only enhances fundamental understanding of receptor biology but also facilitates the development of novel therapeutic strategies targeting glycosylation pathways or specific GPCR glycoforms. Although the functional consequences of glycosylation have been investigated for several decades, delineating their exact structural underpinnings has remained challenging due to the intrinsic flexibility and heterogeneity of carbohydrate structures. Recent advances in structural biology, particularly single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography, have catalyzed a paradigm shift in our understanding of GPCR glycosylation. The integration of these sophisticated structural techniques with biochemical approaches has redefined glycosylation as a complex structural element integral to receptor function. These developments provide a molecular framework for comprehending how glycans influence receptor pharmacology and open new avenues for the rational design of glyco-engineered biologics and allosteric modulators targeting specific extracellular motifs. This mini-review concentrates on glycosylation within the GPCR superfamily, summarizing the impact of glycosylation modifications on receptor function and regulatory mechanisms, recent progress in the structural biology of GPCR glycosylation, and prospective directions for future research in this field.
吴芳明,凌盛龙,石攀,孙玉,田长麟.糖基化修饰对G蛋白偶联受体功能的影响和调控[J].生物化学与生物物理进展,2026,53(9):2352-2364 WU Fang-Ming, LING Sheng-Long, SHI Pan, SUN Yu, TIAN Chang-Lin. Effects and Regulation of Glycosylation Modifications on G Protein-coupled Receptor Function[J]. Progress in Biochemistry and Biophysics,2026,53(9):2352-2364
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