The chymotrypsin-like (CT-L) activity of the proteasome is downregulated by substrates of the peptidyl-glutamyl peptide hydrolyzing (PGPH) activity. To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation and protein degradation assays, these inhibitors revealed that selective PGPH inhibition was insufficient to inhibit protein degradation, indicating that the CT-L and PGPH sites function independently. We also demonstrated that CT-L inhibition by a PGPH substrate does not require the occupancy of the PGPH site or hydrolysis of the PGPH substrate. Thus, these results support a model in which a substrate of one subunit regulates the activity of another via binding to a noncatalytic site(s) rather than through binding to an active site.
|Number of pages||10|
|State||Published - 2001|
Bibliographical noteFunding Information:
This work was supported by the National Institute of Health (GM62120) (C. M. C.) and by an Anderson Postdoctoral Fellowship (J. M.). K. L. is supported by grants awarded by the Swedish Cancer Society, the Swedish Foundation of Strategy Research, and the Hedlund Foundation (Stockholm, Sweden). N. P. D. is supported by a postdoctoral fellowship awarded by the European Commission Training and Mobility Program (ERBFMRXCT960026).
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology