K6非典型泛素化修饰研究进展

Progress in atypical ubiquitination via K6-linkages

摘要:

泛素化是一种存在于真核生物内的蛋白质翻译后修饰，介导了蛋白质的特异性降解与信号转导，参与了诸多生命过程的调控进而影响着机体方方面面的功能。泛素化网络的紊乱和失衡是导致人类严重疾病的重要原因。泛素分子可以形成8种不同拓扑结构的同质泛素链，其丰度和功能差别巨大。目前，丰度较高的K48及K63经典泛素链的修饰底物较多、功能研究相对充分，而其他非典型泛素链的含量低、研究相对较少，但是诸多证据表明非典型泛素链在细胞内发挥着重要的调节功能。K6泛素链是一种重要的非典型泛素链，与K48链相似，具有紧密的空间结构。目前研究发现K6泛素链在DNA损伤修复、线粒体质量控制等过程中发挥重要调节功能，在肿瘤发生、发展以及帕金森疾病的致病过程中有着重要的作用。目前，由于缺乏特异性的K6泛素链抗体和有效的富集手段，导致K6泛素链修饰的底物、调控机制研究相对较少，诸多调控过程和功能有待进一步深入研究。本文系统综述了K6非典型泛素链的结构特征、调控机制以及相关的生物学功能与疾病，为K6泛素链的功能研究提供参考。

关键词:泛素;非典型泛素链;K6泛素链;蛋白质组学;BRCA1/BARD1

Abstract:

Ubiquitination is a post-translational modification of proteins in eukaryotes, which mediates the specific degradation and signal transduction of proteins to regulate a variety of life processes and thus affects functions of the body. The disorder and imbalance of ubiquitination network is a major cause of serious human diseases. Ubiquitin molecules can form eight homogeneous ubiquitin chains with different topological structures, which vary greatly in abundance and function. At present, the classical ubiquitin chains K48 and K63 with high abundance and rich substrates have been intensively studied, while other atypical ubiquitin chains with low content remain to be studied. However, it has been proved that atypical ubiquitin chains play a key role in intracellular regulation. K6 is an important atypical ubiquitin chain, which is similar to K48 chain and has a tight spatial structure. It plays a role in DNA damage repair, mitochondrial quality control, the occurrence and development of tumor, and the pathogenesis of Parkinson's disease. Due to the lack of specific antibodies and effective enrichment methods for K6, little is known about its substrate and regulatory mechanism. This paper systematically reviews the structural characteristics, regulatory mechanism, biological functions, and relevant diseases of atypical K6 linkages, aiming to provide reference for the functional study of K6.

Key words:ubiquitin;atypical ubiquitin chain;K6 ubiquitin chain;proteomics;BRCA1/BARD1