Proline- and arginine-rich peptides as flexible allosteric modulators of human proteasome activity
Małgorzata Giżyńska , Julia Witkowska , Przemysław Karpowicz , Rafał Rostankowski , Estrella Sandra Chocron , Andrew Michael Pickering , Pawel A Osmulski , Maria E. Gaczynska , Elżbieta Jankowska
AbstractProline- and arginine-rich peptide PR11 is an allosteric inhibitor of 20S proteasome. We modified its sequence inter alia by introducing HbYX, RYX or RHbX C-terminal extensions (Hb-hydrophobic moiety, R-arginine, Y-tyrosine, X-any residue). We found that an aromatic penultimate Hb residue improved the inhibitory capacity. Remarkably, the HbYX motif converted the inhibitor into a very good activator, able to stimulate 20S to efficiently degrade protein substrates, such as α-synuclein and enolase. Moreover, the HbYX containing peptide activated proteasome in cultured fibroblasts. The positive and negative PR modulators differently influenced the proteasome conformational dynamics and affected opening of the substrate entry pore. The resolved crystal structure showed PR inhibitor bound far from the active sites, at the proteasome outer face. Our studies indicated moieties crucial for constructing positive and negative modulators of 20S and showed the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.
|Journal series||Journal of Medicinal Chemistry, ISSN 0022-2623, [1520-4804], (N/A 200 pkt)|
|Publication size in sheets||2.3|
|Score||= 200.0, 28-01-2020, ArticleFromJournal|
|Publication indicators||= 1; : 2018 = 1.676; : 2018 = 6.054 (2) - 2018=6.06 (5)|
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