title: 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.
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Nadinath B
authors.initials: NB
authors.lastname: Nillegoda
authors.affiliation: Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirstein
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Szlachcic
authors.affiliation: Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany.
authors.forename: Mykhaylo
authors.initials: M
authors.lastname: Berynskyy
authors.affiliation: 1] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [2] Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Stank
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Stengel
authors.affiliation: Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Arnsburg
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Gao
authors.affiliation: Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Scior
authors.affiliation: 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: D Lys
authors.initials: DL
authors.lastname: Guilbride
authors.affiliation: 1] Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany [2] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [3] Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Mayer
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000517:prevention & control; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D066329:Protein Aggregates