Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family.

Autor: Deshmukh FK; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Ben-Nissan G; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Olshina MA; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Füzesi-Levi MG; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Polkinghorn C; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Arkind G; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Leushkin Y; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Fainer I; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Fleishman SJ; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Tawfik D; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel., Sharon M; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001, Israel. michal.sharon@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 30; Vol. 14 (1), pp. 3126. Date of Electronic Publication: 2023 May 30.
DOI: 10.1038/s41467-023-38404-w
Abstrakt: Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or contain intrinsically disordered regions. This degradation route is tightly controlled by a recently discovered family of proteins named Catalytic Core Regulators (CCRs). Here, we show that CCRs function through an allosteric mechanism, coupling the physical binding of the PSMB4 β-subunit with attenuation of the complex's three proteolytic activities. In addition, by dissecting the structural properties that are required for CCR-like function, we could recapitulate this activity using a designed protein that is half the size of natural CCRs. These data uncover an allosteric path that does not involve the proteasome's enzymatic subunits but rather propagates through the non-catalytic subunit PSMB4. This way of 20S proteasome-specific attenuation opens avenues for decoupling the 20S and 26S proteasome degradation pathways as well as for developing selective 20S proteasome inhibitors.
(© 2023. The Author(s).)
Databáze: MEDLINE
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