Molecular basis for proline- and arginine-rich peptide inhibition of proteasome.
PR39, a naturally occurring and cell-permeable proline- and arginine-rich peptide, blocks the degradation of inhibitor of nuclear factor kappaB (IkappaBalpha), thereby attenuating inflammation. It is a noncompetitive and reversible inhibitor of 20S proteasome. To identify its basis of action, we used solution NMR spectroscopy and mutational analyses of the active fragment, PR11, which identified amino acids required for human 20S proteasome inhibiting activity. We then examined PR11-mediated changes in the expression of nuclear factor kappaB-dependent genes in situ. The results provide prerequisites for proteasome inhibition by proline- and arginine-rich peptides, providing a powerful new tool to investigate inflammatory processes. These findings offer new leads in developing drugs to treat heart diseases or stroke.
Anbanandam
Asokan
A
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, 6431 Fannin St., Houston, TX 77030, USA.
Albarado
Diana C
DC
Tirziu
Daniela C
DC
Simons
Michael
M
Veeraraghavan
Sudha
S
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D050505:Mutant Proteins; D016328:NF-kappa B; C501730:PR 11 proline-arginine-rich peptide; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C072212:PR 39; D002918:Chymotrypsin