Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity

Giżyńska, Małgorzata; Witkowska, Julia; Karpowicz, Przemysław; Rostankowski, Rafał; Chocron, Estrella S.; Pickering, Andrew M.; Osmulski, Pawel; Gaczynska, Maria; Jankowska, Elżbieta

doi:10.1021/acs.jmedchem.8b01025

Title: Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity

Journal Article · 18 November 2018 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.8b01025 · OSTI ID:1557284

Giżyńska, Małgorzata ^[1]; Witkowska, Julia ^[1]; Karpowicz, Przemysław ^[1]; Rostankowski, Rafał ^[1]; Chocron, Estrella S. ^[2]; Pickering, Andrew M. ^[2]; Osmulski, Pawel ^[2]; Gaczynska, Maria ^[2];

^[1]

Univ. of Gdansk (Poland)
Univ. of Texas Health Sciences Center, San Antonio, TX (United States)

Proline- 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). Consequently, we were able to improve inhibitory potency or to convert inhibitors into strong activators: the former with an aromatic penultimate Hb residue and the latter with the HbYX motif. The PR peptide activator stimulated 20S proteasome in vitro to efficiently degrade protein substrates, such as α-synuclein and enolase, but also 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, in the pocket used by natural activators. Overall, our studies indicate the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.

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Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Science Center; USDOE

OSTI ID:: 1557284

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 1 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular Basis for Proline- and Arginine-Rich Peptide Inhibition of Proteasome Anbanandam, Asokan; Albarado, Diana C.; Tirziu, Daniela C. Journal of Molecular Biology, Vol. 384, Issue 1 https://doi.org/10.1016/j.jmb.2008.09.021	journal	December 2008
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Proteasomal dysfunction in aging and Huntington disease Li, Xiao-Jiang; Li, Shihua Neurobiology of Disease, Vol. 43, Issue 1 https://doi.org/10.1016/j.nbd.2010.11.018	journal	July 2011
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Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide Gao, Youhe; Lecker, Stewart; Post, Mark J. Journal of Clinical Investigation, Vol. 106, Issue 3 https://doi.org/10.1172/JCI9826	journal	August 2000
Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein Karpowicz, Przemysław; Osmulski, Paweł A.; Witkowska, Julia PLOS ONE, Vol. 10, Issue 11 https://doi.org/10.1371/journal.pone.0143038	journal	November 2015
Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design Tan, Xiaolin; Osmulski, Pawel; Gaczynska, Maria Current Medicinal Chemistry, Vol. 13, Issue 2 https://doi.org/10.2174/092986706775197926	journal	January 2006
The Proteasome in Health and Disease Jankowska, Elzbieta; Stoj, Julia; Karpowicz, Przemyslaw Current Pharmaceutical Design, Vol. 19, Issue 6 https://doi.org/10.2174/138161281906141012124358	journal	December 2012
Proteins Directly Interacting with Mammalian 20S Proteasomal Subunits and Ubiquitin-Independent Proteasomal Degradation Sánchez-Lanzas, Raúl; Castaño, José Biomolecules, Vol. 4, Issue 4 https://doi.org/10.3390/biom4041140	journal	December 2014

Cited By (6)

Methods to Discover and Evaluate Proteasome Small Molecule Stimulators Coleman, Rachel A.; Trader, Darci J. Molecules, Vol. 24, Issue 12 https://doi.org/10.3390/molecules24122341	journal	June 2019
Proteasome Activation to Combat Proteotoxicity Jones, Corey L.; Tepe, Jetze J. Molecules, Vol. 24, Issue 15 https://doi.org/10.3390/molecules24152841	journal	August 2019
Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity Santoro, Anna Maria; Lanza, Valeria; Bellia, Francesco ChemMedChem, Vol. 15, Issue 3 https://doi.org/10.1002/cmdc.201900612	journal	December 2019
Pipecolic esters as minimized templates for proteasome inhibition Giletto, Matthew B.; Osmulski, Pawel A.; Jones, Corey L. Organic & Biomolecular Chemistry, Vol. 17, Issue 10 https://doi.org/10.1039/c9ob00122k	journal	January 2019
Methods to Discover and Evaluate Proteasome Small Molecule Stimulators Coleman, Rachel A.; Trader, Darci J. Molecules, Vol. 24, Issue 12 https://doi.org/10.3390/molecules24122341	journal	June 2019
Proteasome Activation to Combat Proteotoxicity Jones, Corey L.; Tepe, Jetze J. Molecules, Vol. 24, Issue 15 https://doi.org/10.3390/molecules24152841	journal	August 2019

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60 APPLIED LIFE SCIENCES
Degradation
inhibition
inhibitors
modulators
peptides and proteins

Title: Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity

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