Mixed-class J-domain protein scaffolds promote expanded aggregate handling and multivalent Hsp70 engagement during functional disaggregase assembly.

Anna Szlachcic, Nadinath B Nillegoda

Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Poland.Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Poland. · pubmed

Paper

Abstract

Protein aggregates threaten cellular proteostasis and are linked to aging and disease. In metazoa, aggregate resolution relies on Hsp70-J-domain protein (JDP)-based disaggregases. Previous studies showed human class A and class B JDP assemblies enhance Hsp70-mediated disaggregation, but the underlying mechanism has remained unclear. Using J-domain mutants that impair Hsp70 binding while preserving mixed-class JDP interaction, we show that synergistic disaggregation is lost when either JDP partner cannot engage Hsp70. Size-resolved disaggregation assays further reveal that mixed-class JDP assemblies influence the processing of distinct luciferase aggregate populations, including aggregate species inefficiently handled by either JDP alone. Our findings support a model in which mixed-class JDP assemblies enhance Hsp70 disaggregation through expanded aggregate-processing capacity and multivalent Hsp70 recruitment by both JDP partners.

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Research summary

Mixed-class J-domain protein scaffolds enhance Hsp70-mediated disaggregation by expanding aggregate-processing capacity and enabling multivalent Hsp70 recruitment. This work provides mechanistic insight into fundamental proteostasis maintenance, a core hallmark of aging, though it represents incremental basic science rather than a direct intervention for lifespan extension.

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