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Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain

2004; American Association for the Advancement of Science; Volume: 306; Issue: 5693 Linguagem: Inglês

10.1126/science.1100946

1095-9203

Rati Verma, Noël R. Peters, Mariapina D’Onofrio, Gregory P. Tochtrop, Kathleen M. Sakamoto, Ranjani Varadan, Mingsheng Zhang, Philip Coffino, David Fushman, Raymond J. Deshaies, Randall W. King,

Cancer-related Molecular Pathways

To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked cell cycle progression by inhibiting cyclin B proteolysis and inhibited degradation of ubiquitinated Sic1 by purified proteasomes. Ubistatins blocked the binding of ubiquitinated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of Lys 48 -linked chains. The same interface is recognized by ubiquitin-chain receptors of the proteasome, indicating that ubistatins act by disrupting a critical protein-protein interaction in the ubiquitin-proteasome system.