蛋白酶体调节颗粒的结构生物学特征及其功能

Structural Characteristics and Biological Functions of Proteasome Regulatory Particles

蛋白酶体调节颗粒(regulatory particle,RP)参与调控许多重要信号通路的蛋白质降解,在维持细胞稳态中发挥重要作用。近年来,真核细胞蛋白酶体在癌症治疗中的作用机制及药物研发已引起了广泛关注,并有3种蛋白酶体抑制剂已用于临床治疗。随着蛋白酶体功能研究的不断深入,以及晶体学和冷冻电镜技术在其结构生物学研究中的广泛应用,目前已解析了3类蛋白酶体调节颗粒的原子结构。类型1是保守的调节颗粒19S(PA700);类型2是11S蛋白酶体调节颗粒PA28(PA28α,PA28β,PA28γ)和PA26等;类型3是保守的Blm10/PA200蛋白酶体调节颗粒。其中,类型1以ATP依赖的方式发挥蛋白质降解活性,类型2和类型3以非ATP依赖的方式发挥功能。通过研究3种不同类型蛋白酶体调节颗粒的结构和功能,阐明了蛋白酶体活性调节机制并促进了基于蛋白酶体结构的抑制剂开发。本文以蛋白酶体调节颗粒的结构生物学研究为基础,系统地总结了3类家族蛋白质的结构生物学特征和其调节蛋白酶体活性机制的研究进展,这些将为深入了解蛋白酶体的作用机制及其在癌症治疗领域的药物设计提供重要的参考信息。

Proteasome regulatory particles(RPs)play a vital role in many essential signaling pathways for the regulation of protein degradation and maintenance of cell homeostasis.The mechanism of eukaryotic proteasomes in cancer treatment and drug development has attracted widespread attention.Currently,three proteasome inhibitors are already in use in clinical treatments.There is continuous in-depth research on proteasome structures as well as functions using crystallography and cryo-electron microscopy.Recently,the atomic structure of three types of RPs has been resolved.Type 1 is conservative RP 19 S(PA700).Type 2 is the 11 S RP PA28(PA28α,PA28β,PA28γ)and PA26.Type 3 is a conservative Blm10/PA200 proteasome RP.The Type 1 proteasome RP carries out protein degradation activity in an ATP-dependent manner,types 2 and 3 function in an ATP-independent manner.By studying the structure and function of three different types of proteasome RPs,the mechanism of proteasome activity was clarified and the development of inhibitors based on the structure was promoted.Based on the structural biology research of proteasome RPs,this article systematically summarizes the structural biological characteristics of the three types of proteins and the research progress of their mechanisms of regulation of different cellular processes.This will increase our knowledge about proteasome research developments and will provide important reference information for drug design in cancer treatment.