Nature Chemical Biology
Nature Chemical Biology
5 years ago

Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases
Yaru Zhang, Anton Shostak, Michael Brunner, Ibrahim Avi Cemel, Herbert Tschochner, Frauke Melchior, Amy E Palmer, Nati Ha, Philipp E Merkl, Tobias Schafmeier, Nicolas Stankovic-Valentin, Axel Diernfellner, Kyle P Carter, Walter J Wever, Jing Li, Raymond J Deshaies, Simon Obermeyer, Linda Lauinger, Albert A Bowers
Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2370

DOI: 10.1038/nchembio.2370

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