Bump and Hole modification of IAP antagonist-IAP pairs for a novel protein degradation system
Project Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo
https://tpd.f.u-tokyo.ac.jp/en/
researchmap: https://researchmap.jp/read0160771
PROTAC brings target proteins and E3 ubiquitin ligases into close proximity and induces ubiquitination and degradation of target proteins. We have developed IAP-based PROTACs (SNIPERs) that induce the degradation of various target proteins by recruiting IAPs that form K63-linked poly-ubiquitin chain, making them useful tools for analyzing K63 ubiquitin code. SNIPER utilizes endogenous IAPs (XIAP, cIAP1, etc.) to ubiquitinate target proteins, and most cells express multiple IAP family proteins. Therefore, with the current SNIPER technology, it has not been possible to analyze in detail the ubiquitin chains individual IAPs form and the resulting cellular responses. In this study, IAP antagonist-IAP pairs will be modified by a Bump and Hole method making it possible to analyze IAP functions individually without the influence of endogenous IAPs. We will develop Bump-SNIPERs and analyze the functional differences of six human IAPs family members (cIAP1, cIAP2, XIAP, Livin, ILP2 and Apollon) especially focusing on the ubiquitin chains they form and the degradation mechanisms.
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