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Regulation of human HSC70 ATPase and chaperone activities by Apg2: Role of the acidic subdomain

DOI: 10.1016/j.jmb.2018.11.026 DOI Help

Authors: Yovana Cabrera (Universidad del País Vasco) , Leire Dublang (Universidad del País Vasco) , José Angel Fernández-higuero (Universidad del País Vasco) , David Albesa-jove (CIC bioGUNE; IKERBASQUE) , Maria Lucas (CIC bioGUNE; IBBTEC) , Ana Rosa Viguera (Universidad del País Vasco) , Marcelo E. Guerin (CIC bioGUNE; IKERBASQUE) , Jose M. G. Vilar (Universidad del País Vasco; IKERBASQUE) , Arturo Muga (Universidad del País Vasco) , Fernando Moro (Universidad del País Vasco)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 15304

Abstract: Protein aggregate reactivation in metazoans is accomplished by the combined activity of Hsp70, Hsp40 and Hsp110 chaperones. Hsp110s support the refolding of aggregated polypeptides acting as specialized nucleotide exchange factors of Hsp70. We have studied how Apg2, one of the three human Hsp110s, regulates the activity of Hsc70 (HspA8), the constitutive Hsp70 in our cells. Apg2 shows a biphasic behavior: at low concentration, it stimulates the ATPase cycle of Hsc70, binding of the chaperone to protein aggregates and the refolding activity of the system, while it inhibits these three processes at high concentration. When the acidic subdomain of Apg2, a characteristic sequence present in the substrate binding domain of all Hsp110s, is deleted, the detrimental effects occur at lower concentration and are more pronounced, which concurs with an increase in the affinity of the Apg2 mutant for Hsc70. Our data support a mechanism in which Apg2 arrests the chaperone cycle through an interaction with Hsc70(ATP) that might lead to premature ATP dissociation before hydrolysis. In this line, the acidic subdomain might serve as a conformational switch to support dissociation of the Hsc70:Apg2 complex.

Keywords: Apg2; Hsp110; Hsc70; Chaperone complex; Aggregate reactivation

Subject Areas: Biology and Bio-materials


Beamlines: B21-High Throughput SAXS

Other Synchrotrons: SOLEIL