title: Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride.
abstract: The Saccharomyces cerevisiae AAA+ protein Hsp104 and its Escherichia coli counterpart ClpB cooperate with Hsp70 chaperones to refold aggregated proteins and fragment prion fibrils. Hsp104/ClpB activity is regulated by interaction of the M-domain with the first ATPase domain (AAA-1), controlling ATP turnover and Hsp70 cooperation. Guanidinium hydrochloride (GdnHCl) inhibits Hsp104/ClpB activity, leading to prion curing. We show that GdnHCl binding exerts dual effects on Hsp104/ClpB. First, GdnHCl strengthens M-domain/AAA-1 interaction, stabilizing Hsp104/ClpB in a repressed conformation and abrogating Hsp70 cooperation. Second, GdnHCl inhibits continuous ATP turnover by AAA-1. These findings provide the mechanistic basis for prion curing by GdnHCl.
authors: Zentrum für Molekulare Biologie der Universität Heidelberg and Deutsches Krebsforschungszentrum, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.
authors: Eva
authors: E
authors: Kummer
authors: Yuki
authors: Y
authors: Oguchi
authors: Fabian
authors: F
authors: Seyffer
authors: Bernd
authors: B
authors: Bukau
authors: Axel
authors: A
authors: Mogk
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D049071:Endopeptidase Clp; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D019791:Guanidine / Q000737:chemistry / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D008856:Microscopy, Fluorescence; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D054730:Protein Interaction Domains and Motifs; D058849:Protein Refolding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011328:Prions; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D000255:Adenosine Triphosphate; D008156:Luciferases; D049071:Endopeptidase Clp; C069775:ClpB protein, E coli; D019791:Guanidine