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Total chemical and semisynthetic approaches for the preparation of ubiquitinated proteins and their applications

Science China Chemistry 2018年第3期61卷 251-265页

作者： Xiaobao Bi Kalyan Kumar Pasunooti Chuan-Fa Liu School of Biological Sciences Nanyang Technological University

Protein ubiquitination is an important post-translational modification(PTM) in eukaryotic organisms that regulates a variety of cellular processes, such as protein degradation, signal transduction, apoptosis, and DNA damage tolerance. To decipher mechanistically the diverse biological functions of ubiquitination, homogeneous ubiquitinated proteins are greatly *** direct isolation from cell source and in vitro enzymatic methods can be used to produce such proteins, these methods often suffer from problems of low yield or heterogeneous products. Comparably, total chemical and semisynthetic approaches offer good alternatives to produce the ubiquitinated proteins with high purity and selectivity. This review summarizes the recent developments of protein ubiquitination strategies and the use of the synthesized proteins to help garner structural and functional insight into the inner workings of the ubiquitin system.

关键词： ubiquitination native chemical ligation deubiquitinases protein synthesis

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Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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Genes & Diseases 2024年第5期11卷 140-162页

作者： Xudong Li Wei Li Yanli Zhang Linping Xu Yongping Song Department of Hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China

The advent of tyrosine kinase inhibitors(TKI)targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia(CML),greatly prolonged the life of CML patients,and improved their ***,TKI resistance is still a major problem with CML patients,reducing the efficacy of treatment and their quality of *** resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent ***,the main clinical strategy addressing TKI resistance is to switch to newly developed ***,data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance ***,finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system(UPS)has emerged as a *** UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological *** recent years,the study of UPS in hematological malignant tumors has resulted in effective treatments,such as bortezomib in the treatment of multiple myeloma and mantle cell *** CML,the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL,interfering with CML-related signaling pathways,and negatively or positively affecting leukemia stem *** of these molecules may help overcome TKI resistance and treat *** this review,the mechanism of TKI resistance is briefly described,the components of UPS are introduced,existing studies on UPS participating in TKI resistance are listed,and UPS as the therapeutic target and strategies are discussed.

关键词： Chronic myeloid leukemia deubiquitinases E3 ligase PROTAC TKI resistance Ubiquitin-proteasome system

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Structural insights into the activation of ubiquitin-specific protease 46 by WDR48 and WDR20

Structural insights into the activation of ubiquitin-specifi...

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中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年

作者： Hanwen Zhu Tianlong Zhang Fang Wang Jun Yang Jianping Ding State Key Laboratory of Molecular Biology National Center for Protein Science Shanghai Shanghai Science Research Center CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology University of Chinese Academy of Sciences Chinese Academy of Sciences

Ubiquitination is an important and reversible post-translational modification that regulates the stability, localization and function of proteins in many cellular processes. deubiquitinases are responsible for the removal of ubiquitin chains from proteins, and ubiquitin-specific proteases(USPs) are the largest family of deubiquitinases, some of which are regulated by WD40-repeat proteins. The deubiquitinating activity of USP46 can be activated by WDR48 and WDR20;however, the molecular mechanism remains elusive. We determined the crystal structure of the USP46-WDR48-WDR20 complex at 3.1 ? resolution and validated the functional roles of key residues involved in the assembly of the complex with both in vitro and in vivo functional assays. The structural and functional data demonstrate that the binding of WDR48 and WDR20 can activate the activity of USP46 independently and synergistically and plays an indispensible role in USP46-mediated deubiquitination of PHLPP1 in the Akt signaling pathway. Detailed comparison of all available USP46 and USP12 structures reveals that the WDR48 binding not only stabilizes the Fingers subdomain but also increases conformational flexibility of several structural elements surrounding the catalytic center;and the combined effects render a moderate activation of the USPs. The further binding of WDR20 largely restores the WDR48-binding induced conformational changes and stabilizes the conformations of those structural elements surrounding the catalytic center, and thus potentiates the activity of the USPs. These results provide new insights into the molecular mechanism of the activation of USPs by WD40-repeat proteins.

关键词： Ubiquitination deubiquitinases ubiquitin-specific proteases USP46 WD40-repeat protein allosteric regulation

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