生物大分子相分离领域的研究进展回顾与展望

Biomolecular phase separation research:Milestones,insights,and future trajectories

蛋白质和核酸等生物大分子通过相分离在细胞特定区域富集,形成无生物膜包被的生物分子凝聚体,也称无膜细胞器,为细胞实现了精细区室化.生物大分子相分离由分子间复杂而又特异的多价相互作用驱动,所形成的无膜细胞器具有独特的物理特性,如流动性、融合与分裂能力、表面张力等.将相分离理论引入生物学研究,为深入理解生命活动的分子机制提供了新颖的视角.近年来的研究揭示了生物大分子相分离在众多基本生物过程中的作用,包括稳定染色质结构、调节基因表达、调控RNA加工、成熟及蛋白质翻译等.此外,相分离动态灵活的特征也使其成为细胞响应内外信号刺激,以及不同细胞类型维持特异亚细胞结构的一种重要方式.本综述回顾了从生物大分子相分离发现至今的研究进展:首先概述了无膜细胞器的早期研究历史,旨在梳理相分离理论引入前无膜细胞器的研究脉络;其次探讨了相分离的分子机制及生物分子凝聚体的理化性质,阐释了串联重复结构域和内在无序区域介导的两种相分离发生机制,并引申出其理化性质与生物功能的相关性;后续重点讨论了无膜细胞器的众多生物学功能,突出了无膜细胞器在不同细胞不同环境中功能的多样性和特异性;最后总结了相分离领域内亟需回答的问题,并展望了未来领域在成分分析、基础理论、细胞功能、疾病关系、药物开发以及新技术应用等方面的研究前景.

Biological macromolecules such as proteins and nucleic acids undergo phase separation to form biomolecular condensates,achieving precise compartmentalization within cells and spatial-temporal regulation of various biological functions.Unlike membrane-bound organelles,biomolecular condensates lack a biological membrane but instead rely on complex multivalent interactions among molecules to dynamically separate them from the surrounding environment.These condensates exhibit both relative stability and intricate structural features rich in dynamic changes.They possess unique physical properties akin to liquids,such as fluidity,fusion,and fission capabilities.The introduction of phase separation has provided a novel and insightful perspective for deeply understanding the molecular mechanisms in biology.Recent studies have uncovered the vital biological roles played by biomolecular phase separation.Phase separation can be classified into three groupls based on their occurance in different cellular contexts:universally present phase separation,environmentally induced phase separation,and cell-type-specific phase seapration.Universally present phase separation encompasses fundamental cellular processes including chromatin organization,gene expression regulation,RNA processing and maturation,and protein translation control.Enviromentally induced phase separation plays a crucial role in cell’s response to external stimuli,demonstrating its importance in maintaining cellular homeostasis and adaptability in response to changing physiological conditions.Additionally,cell-type-specific phase separation contribute significantly in mediating cell-cell connections and modulating synaptic structures and functions.This review traces the research advancements of research in this field,from the early investigations into membraneless organelles to the more recent developments in phase separation.It begins with the early research history of membrane-less organelles prior to the advent of phase separation theory,aiming to trace the research trajectory before the introduction of phase separation theory.Then it delves into the molecular mechanism of phase separation,particularly those mediated by tandem repeat domains and intrinsically disordered regions,with emphasis on the correlation between their physicochemical properties and the functional roles of condensates.Subsequently,the focuses shifts to the diverse biological functions of biomolecular phase separation,emphasizing their functional diversity and specificity in diverse cellular environments.Finally,the review concludes by identifying pressing questions within the field of biomolecular phase separation and outlining promising avenues for future research.These include further analysis of membraneless organelles compositions,the exploration of fundamental theories governing phase separation,the elucidation of the relationships between condensates and cellular functions,the depiction of the intricate internal structure of membraneless organelles and the interactions between them,and the development of novel technologies to further our understanding of this fascinating and complex biological phenomenon.Additionally,research should focus on the investigation of links between phase separation and disease as well as therapeutic approaches targeting phase separation mechanisms.As research progresses,the continued investigation of membraneless organelles is poised to advance our knowledge of cellular biology and inspire new therapeutic strategies.