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Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

Abstract:

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.

Note:
Methodology developed in VLN was applied to predict protein-protein complexes. The application of these new methods were key to simulate protein complexes of co-chaperone Hsp40 molecules and helped to understand the specificity of transient complexation of the highly flexible J-proteins. These findings helped to uncover the mechanism by which human cells dissolve aggregated proteins. Misfolded and clumped proteins are potentially toxic and linked to a large number of human diseases, for example, metabolic disorders.

10.1038/nature14884

Projects: A3.2: Cross-talk of signaling pathways and endocytic machinery in hepato...

Nature
Nature 524(7564) : 247
5th Aug 2015

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

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[Antonia Stank] [Rebecca Wade]

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Views: 1142
  • Created: 18th Sep 2015 at 13:35
  • Last updated: 18th Sep 2015 at 13:41

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