Crucial HSP70 co–chaperone complex unlocks metazoan protein disaggregation

By Nadinath B. Nillegoda, J. Kirstein, Anna Szlachcic, M. Berynskyy, Antonia Stank, Florian Stengel, Kristin Arnsburg, Xuechao Gao, Annika Scior, R. Aebersold and 5 more. Nature, 2015

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Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, 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 systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. 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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/939a39ebfba96e297269a15631673074a70f5a0b

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Citations in the corpus

In vivo aspects of protein folding and quality control (2016, methodology): “by the UPS requires disaggregation prior to degradation, which is performed by Hsp70 in cooperation with Hsp110 and a mixed-class Hsp40 complex (77, 78) (Fig.”
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, background): “Novel and previously unappreciated functions of chaperones in higher eukaryotes have been shown to be the binding to preformed aggregates to promote their disassembly (216), to mask their hydrophobic patches (217, 218), or to convert them into large assemblies (206, 207), therefore preventing their ”