title: Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding.
abstract: Small heat shock proteins (sHsp) constitute an evolutionary conserved yet diverse family of chaperones acting as first line of defence against proteotoxic stress. sHsps coaggregate with misfolded proteins but the molecular basis and functional implications of these interactions, as well as potential sHsp specific differences, are poorly explored. In a comparative analysis of the two yeast sHsps, Hsp26 and Hsp42, we show in vitro that model substrates retain near-native state and are kept physically separated when complexed with either sHsp, while being completely unfolded when aggregated without sHsps. Hsp42 acts as aggregase to promote protein aggregation and specifically ensures cellular fitness during heat stress. Hsp26 in contrast lacks aggregase function but is superior in facilitating Hsp70/Hsp100-dependent post-stress refolding. Our findings indicate the sHsps of a cell functionally diversify in stress defence, but share the working principle to promote sequestration of misfolding proteins for storage in native-like conformation.
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ungelenk
authors.affiliation: FOM Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, Amsterdam 1098 XG, The Netherlands.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Moayed
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
authors.forename: Chi-Ting
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
authors.forename: Tomas
authors.identifier: 0000-0002-6996-1323
authors.initials: T
authors.lastname: Grousl
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Scharf
authors.affiliation: FOM Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, Amsterdam 1098 XG, The Netherlands.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mashaghi
authors.affiliation: FOM Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, Amsterdam 1098 XG, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Tans
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.
authors.forename: Matthias P
authors.identifier: 0000-0002-7859-3112
authors.initials: MP
authors.lastname: Mayer
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Mogk
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
mesh_terms: D019610:Cytoprotection / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000502:physiology*; D050888:Heat-Shock Proteins, Small / Q000502:physiology*; D018869:Heat-Shock Response / Q000502:physiology; D008291:Malate Dehydrogenase / Q000378:metabolism; D009154:Mutation; D066329:Protein Aggregates / Q000502:physiology; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology*
chemical_list: C499528:HSP26 protein, S cerevisiae; C098005:HSP42 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D066329:Protein Aggregates; D029701:Saccharomyces cerevisiae Proteins; D008291:Malate Dehydrogenase