泛素连接酶
细胞生物学
泛素
亨廷顿蛋白
化学
生物
HEK 293细胞
蛋白质降解
机制(生物学)
修剪
亨廷顿蛋白
受体
生物化学
基因
突变体
计算机科学
哲学
操作系统
认识论
作者
Jingwei Zeng,Ana Filipa Santos,Aamir S. Mukadam,Mariana Osswald,David A. Jacques,Claire F. Dickson,Stephen H. McLaughlin,C.M. Johnson,L. Kiss,Jakub Lupták,Nadine Renner,Marina Vaysburd,William A. McEwan,Eurico Morais‐de‐Sá,Dean Clift,Leo C. James
标识
DOI:10.1038/s41594-021-00560-2
摘要
Trim-Away is a recently developed technology that exploits off-the-shelf antibodies and the RING E3 ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically activated upon target engagement, either during its normal immune function or when repurposed for targeted protein degradation, is unknown. Here we show that a mechanism of target-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce virus neutralization or drive Trim-Away. We harness this mechanism for selective degradation of disease-causing huntingtin protein containing long polyglutamine tracts and expand the Trim-Away toolbox with highly active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has implications for targeted protein degradation technologies.
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