Nub1 traps unfolded FAT10 for ubiquitin-independent degradation by the 26S proteasome.

Autor:	Arkinson C; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA94720, USA.; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA94720, USA.; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA94720, USA., Dong KC; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA94720, USA., Gee CL; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA94720, USA.; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA94720, USA.; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA94720, USA., Costello SM; Biophysics Graduate Program, University of California, Berkeley, CA, USA., Marqusee S; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA94720, USA.; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA94720, USA.; Department of Chemistry, University of California, Berkeley, CA, USA.; Chan Zuckerberg Biohub, San Francisco, CA, USA., Martin A; California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA94720, USA.; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA94720, USA.; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA94720, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 12. Date of Electronic Publication: 2024 Jun 12.
DOI:	10.1101/2024.06.12.598715
Abstrakt:	The ubiquitin-like modifier FAT10 targets hundreds of proteins in the mammalian immune system to the 26S proteasome for degradation. This degradation pathway requires the cofactor Nub1, yet the underlying mechanisms remain unknown. Here, we reconstituted a minimal in vitro system and revealed that Nub1 utilizes FAT10's intrinsic instability to trap its N-terminal ubiquitin-like domain in an unfolded state and deliver it to the 26S proteasome for engagement, allowing the degradation of FAT10-ylated substrates in a ubiquitin- and p97-independent manner. Through hydrogen-deuterium exchange, structural modeling, and site-directed mutagenesis, we identified the formation of a peculiar complex with FAT10 that activates Nub1 for docking to the 26S proteasome, and our cryo-EM studies visualized the highly dynamic Nub1 complex bound to the proteasomal Rpn1 subunit during FAT10 delivery and the early stages of ATP-dependent degradation. These studies thus identified a novel mode of cofactor-mediated, ubiquitin-independent substrate delivery to the 26S proteasome that relies on trapping partially unfolded states for engagement by the proteasomal ATPase motor. Competing Interests: Competing interests: The authors declare no competing interests.
Databáze:	MEDLINE
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