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J Mol Biol. 2019 Jan 18;431(2):444-461. doi: 10.1016/j.jmb.2018.11.026. Epub 2018 Dec 4.

Regulation of Human Hsc70 ATPase and Chaperone Activities by Apg2: Role of the Acidic Subdomain.

Author information

1
Instituto Biofisika (UPV/EHU, CSIC) y Dpto. de Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Barrio Sarriena S/N, 48490, Leioa, Spain.
2
Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
3
Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain; IBBTEC, C/ Albert Einstein 22, PCTCAN, 39011 Santander, Spain.
4
Instituto Biofisika (UPV/EHU, CSIC) y Dpto. de Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Barrio Sarriena S/N, 48490, Leioa, Spain; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
5
Instituto Biofisika (UPV/EHU, CSIC) y Dpto. de Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Barrio Sarriena S/N, 48490, Leioa, Spain. Electronic address: fernando.moro@ehu.es.

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; Hsc70; Hsp110; aggregate reactivation; chaperone complex

PMID:
30521813
DOI:
10.1016/j.jmb.2018.11.026

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