蛋白质水解
嵌合体(遗传学)
化学
细胞生物学
计算生物学
生物
生物化学
酶
基因
作者
Constanza Salinas-Rebolledo,Javier Blesa,Guillermo Valenzuela Nieto,David Schwefel,Natalia López González del Rey,Maxs Méndez-Ruette,James L. Burkhalter,Luis Federico Bátiz,Ronald Jara,José Á. Obeso,Pedro Chaná‐Cuevas,Gopal P. Sapkota,Alejandro Rojas‐Fernández
标识
DOI:10.1101/2024.03.08.584142
摘要
Abstract The p97 protein is a member of the AAA + family of ATPases. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products of p97 are presented to the 26S Proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. We have engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 Adapter FAF1. In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis.
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