Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

Nadinath B. Nillegoda, Janine Kirstein, Anna Szlachcic, Mykhaylo Berynskyy, Antonia Stank, Florian Stengel, Kristin Arnsburg, Xuechao Gao, Annika Scior, Ruedi Aebersold, D. Lys Guilbride, Rebecca C. Wade, Richard I. Morimoto, Matthias P. Mayer, Bernd Bukau

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states1,2. Healthy metazoan cells effectively eliminate intracellular protein aggregates3,4, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems5,6, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro4,7. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.

Original languageEnglish (US)
Pages (from-to)247-251
Number of pages5
JournalNature
Volume524
Issue number7564
DOIs
StatePublished - Aug 13 2015

ASJC Scopus subject areas

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    Nillegoda, N. B., Kirstein, J., Szlachcic, A., Berynskyy, M., Stank, A., Stengel, F., Arnsburg, K., Gao, X., Scior, A., Aebersold, R., Guilbride, D. L., Wade, R. C., Morimoto, R. I., Mayer, M. P., & Bukau, B. (2015). Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature, 524(7564), 247-251. https://doi.org/10.1038/nature14884