Jankowska, E.; Gaczynska, M.; Osmulski, P.; Sikorska, E.; Rostankowski, R.; Madabhushi, S.; Tokmina-Lukaszewska, M.; Kasprzykowski, F.

Biopolymers (2010), 93(5), 481-495 CODEN: BIPMAA; ISSN: 0006-3525. English.

Proteasome, consisting of a tube-shaped proteolytic core particle and attached to it regulatory modules, is a multifunctional enzymic complex essential for the ubiquitin-proteasome metabolic pathway. Due to its immense involvement in regulation of cellular physiol., the proteasome is an acknowledged anticancer drug target and potential target to treat inflammatory or degenerative diseases. So far, competitive inhibitors of the core particle gain most consideration as drugs. We postulate that noncompetitively-acting small-mol. compds. would provide excellent means to precisely regulate actions of the proteasome. In this study, we evaluated five short peptides based on sequences of two proteins known to interact with the core proteasome: HIV-1 Tat and PA28/REG activator. We performed CD, Fourier Transformed IR Spectroscopy (FTIR), and NMR anal., supplemented by MD simulations, and tested influence of the peptides on performance of the core particle active sites and functioning of regulatory modules. We found that PP2-containing Tat peptides are noncompetitive inhibitors of the core, interfering with the actions of PA28.alpha..beta. activator. In addition, at low concns. the turn-prone Tat2 is able to activate the latent core. The random coil-structured PA28-derived peptides display only weak or nondetectable direct effects on the core activities, exhibiting, however, a pos. cooperation with activity-enhancing actions of PA28.alpha..beta.. .COPYRGT. 2010 Wiley Periodicals, Inc.