Potential allosteric modulators of the proteasome activity.
Proteasome, consisting of a tube-shaped proteolytic core particle and attached to it regulatory modules, is a multifunctional enzymatic complex essential for the ubiquitin-proteasome metabolic pathway. Due to its immense involvement in regulation of cellular physiology, 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-molecule compounds 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 Circular Dichroism (CD), Fourier Transformed Infrared Spectroscopy (FTIR), and Nuclear Magnetic Resonance (NMR) analysis, 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 PA28alphabeta activator. In addition, at low concentrations 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 positive cooperation with activity-enhancing actions of PA28alphabeta.
Jankowska
E
E
Faculty of Chemistry, University of Gdansk, Sobieskiego 18, Gdansk 80-952, Poland. elaj@chem.univ.gda.pl
Gaczynska
M
M
Osmulski
P
P
Sikorska
E
E
Rostankowski
R
R
Madabhushi
S
S
Tokmina-Lukaszewska
M
M
Kasprzykowski
F
F
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D004912:Erythrocytes / Q000201:enzymology; D015497:HIV-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
D010446:Peptide Fragments; D046988:Proteasome Endopeptidase Complex