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.
Other publications of the same journal or congress with authors from the University of Cantabria
