诱导同源蛋白质二聚化的方法

Methods for Inducing Homologous Protein Dimerization

同源蛋白质二聚化是一种普遍的现象,在许多生物过程中发挥着关键作用。多数细胞事件,如信号转导、转录辅因子募集、酶激活,甚至致病途径,都通过同源蛋白质-蛋白质相互作用受到显著调节。调控同源蛋白质二聚化过程和了解其分子机制对于生物医学应用以及剖析复杂的生物调控网络至关重要。邻近效应或分子的物理接近效应是生物过程中必不可少的调节因素,可以通过诱导二聚化方法来控制。基于临近诱导的化学诱导二聚化(chemically induced dimerization,CID)系统与光诱导二聚化(light induced dimerization,LID)系统为调节二聚化蛋白质的功能提供了强大的工具,并得到逐步发展。近年来,金属离子、核酸和分子主客体系统被提出作为正交控制同源蛋白质二聚化的新方法。本综述阐述了通过CID系统、LID系统以及超分子化学的手段诱导同源蛋白质二聚化的方法与应用,以期为今后同源蛋白质二聚化的应用发展提供一些参考与思路。

Proteins in biological systems rarely act alone,but instead bind with other biomolecules to trigger specific cellular reactions.These biomolecules are usually astonishing number of proteins self-assemble to form dimers,which are both in a relatively isolated state and in a protein interaction network and cascade.Dimerization can endow proteins with various structural and functional advantages,including improving stability,controlling the accessibility and specificity of active sites,and increasing complexity.The self-association of proteins to form dimers is a very common phenomenon,and the functional importance of homologous protein dimerization cannot be overestimated.It provides diversity and specificity in many pathways,and most cellular events,such as signal transduction,transcription cofactor recruitment,enzyme activation,and even pathogenic pathways,are significantly regulated through homologous protein-protein interactions.The regulation of protein dimerization is an important process for the growth and development of organisms under internal or external stimuli in the natural environment.Therefore,regulating the dimerization process of homologous proteins and understanding their molecular mechanisms are crucial for biomedical applications and analyzing complex biological regulatory networks.Proximity effects or physical proximity effects of molecules are essential regulatory factors in biological processes,which can be controlled through induced dimerization methods.The application range of induced proximity ranges from manipulating protein folding,activation,localization,and degradation to controlling gene transcription or cell therapy.The chemical induced dimerization(CID)system and light induced dimerization(LID)system based on proximity induction provide powerful tools for regulating the function of dimerized proteins,and have been gradually developed.The concept of CID was proposed as early as 1993.The basic principle of CID is that a small molecule controls the dimerization of a pair of proteins or domains,while binding two proteins and bringing them closer together.Small molecules in the CID system form ternary complexes with target proteins,which can bind to various sites,including“hotspot”and“allosteric sites”.Small molecules play a role by regulating protein proximity.The light induced dimerization system uses photosensitive proteins to undergo conformational changes under light,thereby inducing protein interactions.Multiple photosensitive proteins derived from plants and microorganisms can undergo photo induced homologous interactions,and relying on LID systems,they can be used to study various biological processes,including cell signal transduction,microbial synthesis,and biomedical applications.In recent years,metal ions,nucleic acids,and molecular host guest systems have been proposed as new methods for orthogonal control of homologous protein dimerization,expanding the development and application of dimerization systems.In addition,the chemooptogenetic approach combines the advantages of CID and LID systems and has also been applied in inducing protein dimerization.This review elaborates on the methods and applications of inducing homodimerization of proteins through CID system,LID system,and supramolecular chemistry,while discussing the advantages and disadvantages of dimerization systems.The development direction of dimerization systems is also discussed,in order to provide some reference and ideas for the future application and development of homologous protein dimerization.