Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Quick Search
My eDoc
Session History
Support Wiki
Direct access to
document ID:

          Institute: MPI für medizinische Forschung     Collection: Jahbruch 2014_archival     Display Documents

ID: 681475.0, MPI für medizinische Forschung / Jahbruch 2014_archival
The molecular mechanism of Hsp100 chaperone inhibition by the prion curing agent
guanidinium chloride
Translation of Title:The molecular mechanism of Hsp100 chaperone inhibition by the prion curing agent
guanidinium chloride
Authors:Zeymer, Cathleen; Werbeck, Nicolas; Schlichting, Ilme; Reinstein, Jochen
Date of Publication (YYYY-MM-DD):2013-03-08
Title of Journal:Journal of Biological Chemistry
Journal Abbrev.:J. Biol. Chem.
Issue / Number:10
Start Page:7065
End Page:7076
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:The Hsp100 chaperones ClpB and Hsp104 utilize the energy from ATP hydrolysis to reactivate aggregated proteins in concert with the DnaK/Hsp70 chaperone system, thereby playing an important role in protein quality control. They belong to the family of AAA+ proteins (ATPases associated with various cellular activities), possess two nucleotide binding domains per monomer (NBD1 and NBD2) and oligomerize into hexameric ring complexes. Furthermore, Hsp104 is involved in yeast prion propagation and inheritance. It is well established that low concentrations of guanidinium chloride (GdmCl) inhibit the ATPase activity of Hsp104 leading to so called prion curing, the loss of prion−related phenotypes. Here, we present mechanistic details about the Hsp100 chaperone inhibition by GdmCl using the Hsp104 homolog ClpB from T. thermophilus. Initially, we demonstrate that NBD1 of ClpB, which was previously considered inactive as a separately expressed construct, is a fully active ATPase on its own. Next, we show that only NBD1, but not NBD2, is affected by GdmCl. We present a crystal structure of ClpB NBD1 in complex with GdmCl and ADP, showing that the Gdm+ ion binds specifically to the active site of NBD1. A conserved essential glutamate residue is involved in this interaction. Additionally, Gdm+ interacts directly with the nucleotide, thereby increasing the nucleotide binding affinity of NBD1. We propose that both the interference with the essential glutamate as well as the modulation of nucleotide binding properties in NBD1 is responsible for the GdmCl−specific inhibition of Hsp100 chaperones
Free Keywords:Hsp104, ClpB, AAA+ protein, molecular chaperone, protein structure, kinetics, guanidinium
chloride, ATP hydrolysis, inhibition, prion curing
External Publication Status:published
Document Type:Article
Communicated by:wkaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biophysik
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen/Molecular chaperones
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen/Coherent diffractive imaging
Full Text:
Sorry, no privileges
The scope and number of records on eDoc is subject to the collection policies defined by each institute - see "info" button in the collection browse view.