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Emerging potential of ubiquitin-specific proteases and ubiquitinspecific proteases inhibitors in breast cancer treatment

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World Journal of Clinical Cases 2022年第32期10卷 11690-11701页

作者： Mei-Ling Huang Guang-Tai Shen Nan-Lin Li Department of Thyroid Breast and Vascular SurgeryXijing HospitalThe Fourth Military Medical UniversityXi’an 710032Shaanxi ProvinceChina Department of Breast Surgery Xing'an League People's HospitalUlanhot 137400Inner Mongolia Autonomous RegionChina

Breast cancer is the most frequently diagnosed cancer in women,accounting for 30%of new diagnosing female *** evidence suggests that ubiquitin and ubiquitination played a role in a number of breast cancer etiology and progression *** the primary deubiquitinases in the family,ubiquitin-specific peptidases(USPs)are thought to represent potential therapeutic *** role of ubiquitin and ubiquitination in breast cancer,as well as the classification and involvement of USPs are discussed in this review,such as USP1,USP4,USP7,USP9X,USP14,USP18,USP20,USP22,USP25,USP37,and *** reported USPs inhibitors investigated in breast cancer were also summarized,along with the signaling pathways involved in the investigation and its study *** no USP inhibitor has yet been approved for clinical use,the biological efficacy indicated their potential in breast cancer *** the improvements in phenotypic discovery,we will know more about USPs and USPs inhibitors,developing more potent and selective clinical candidates for breast cancer.

关键词： ubiquitin-specific proteases USPs inhibitors Breast cancer Review

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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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