Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain.
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.
Department of Biology, Howard Hughes Medical Institute (HHMI), California Institute of Technology, Pasadena, CA 91125, USA.
Rati
R
Verma
Noel R
NR
Peters
Mariapina
M
D'Onofrio
Gregory P
GP
Tochtrop
Kathleen M
KM
Sakamoto
Ranjani
R
Varadan
Mingsheng
M
Zhang
Philip
P
Coffino
David
D
Fushman
Raymond J
RJ
Deshaies
Randall W
RW
King
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002457:Cell Extracts; D019926:Cyclin B / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D007399:Interphase; D008938:Mitosis; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013425:Sulfanilic Acids / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D014982:Xenopus laevis
D002457:Cell Extracts; D019926:Cyclin B; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D011804:Quinolines; D011993:Recombinant Fusion Proteins; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013425:Sulfanilic Acids; D025801:Ubiquitin; C492595:ubistatin A; C492596:ubistatin B; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D009955:Ornithine Decarboxylase