TY - JOUR
T1 - Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity
AU - Gizyńska, Małgorzata
AU - Witkowska, Julia
AU - Karpowicz, Przemysław
AU - Rostankowski, Rafał
AU - Chocron, Estrella S.
AU - Pickering, Andrew M.
AU - Osmulski, Pawel
AU - Gaczynska, Maria
AU - Jankowska, Elzbieta
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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. Our studies indicate the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.
AB - 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. Our studies indicate the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.
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U2 - 10.1021/acs.jmedchem.8b01025
DO - 10.1021/acs.jmedchem.8b01025
M3 - Article
C2 - 30452262
AN - SCOPUS:85058220234
SN - 0022-2623
VL - 62
SP - 359
EP - 370
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -