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

Fanindra Kumar Deshmukh, Gili Ben-Nissan, Maya A. Olshina, Maria G. Füzesi-Levi, Caley Polkinghorn, Galina Arkind, Yegor Leushkin, Irit Fainer, Sarel J. Fleishman, Dan Tawfik and Michal Sharon ()
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Fanindra Kumar Deshmukh: Weizmann Institute of Science
Gili Ben-Nissan: Weizmann Institute of Science
Maya A. Olshina: Weizmann Institute of Science
Maria G. Füzesi-Levi: Weizmann Institute of Science
Caley Polkinghorn: Weizmann Institute of Science
Galina Arkind: Weizmann Institute of Science
Yegor Leushkin: Weizmann Institute of Science
Irit Fainer: Weizmann Institute of Science
Sarel J. Fleishman: Weizmann Institute of Science
Dan Tawfik: Weizmann Institute of Science
Michal Sharon: Weizmann Institute of Science

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38404-w

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