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Fine-tuning of the Hsc70-based human protein disaggregase machinery by the distinctive C-terminal extension of Apg2

DOI: 10.1016/j.jmb.2022.167841 DOI Help

Authors: Yovana Cabrera (Universidad del País Vasco; University of Gothenburg) , Ganeko Bernardo-Seisdedos (CIC bioGUNE) , Leire Dublang (Universidad del País Vasco) , David Albesa-Jove (Universidad del País Vasco; Ikerbasque, Basque Foundation for Science) , Natalia Orozco (Fundación Biofísica Bizkaia) , Ana Rosa Viguera (Universidad del País Vasco) , Oscar Millet (CIC bioGUNE) , 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 , VOL 47

State: Published (Approved)
Published: September 2022
Diamond Proposal Number(s): 21035

Open Access Open Access

Abstract: Apg2, one of the three cytosolic Hsp110 chaperones in humans, supports reactivation of unordered and ordered protein aggregates by Hsc70 (HspA8). Together with DnaJB1, Apg2 serves to nucleate Hsc70 molecules into sites where productive entropic pulling forces can be developed. During aggregate reactivation, Apg2 performs as a specialized nucleotide exchange factor, but the origin of its specialization is poorly defined. Here we report on the role of the distinctive C-terminal extension present in Apg2 and other metazoan homologs. We found that the first part of this Apg2 subdomain with propensity to adopt α-helical structure interacts with the nucleotide binding domain of Hsc70 in a nucleotide-dependent manner, contributing significantly to the stability of the Hsc70:Apg2 complex. Moreover, the second intrinsically disordered segment of Apg2 C-terminal extension plays an important role as a downregulator of nucleotide exchange. An NMR analysis showed that the interaction with Hsc70 nucleotide binding domain modifies the chemical environment of residues located in important functional sites such as the interface between lobe I and II and the nucleotide binding site. Our data indicate that Apg2 C-terminal extension is a fine-tuner of human Hsc70 activity that optimizes the substrate remodeling ability of the chaperone system.

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS

Added On: 28/09/2022 13:48

Documents:
1-s2.0-S0022283622004612-main.pdf

Discipline Tags:

Biophysics Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)