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Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction.

The excessive accumulation of misfolded protein aggregates can overwhelm the cell's "quality control" machinery, leading to cell death. The yeast Hsp104 protein and its bacterial homolog ClpB are molecular chaperones that can "rescue" aggregated proteins by coupling the force generated from adenosin... Full description

Journal Title: Science (New York N.Y.), March 1, 2013, Vol.339(6123), pp.1080-1083
Main Author: Rosenzweig, Rina
Other Authors: Moradi, Shoeib , Zarrine-Afsar, Arash , Glover, John R , Kay, Lewis E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1095-9203 ; DOI: 10.1126/science.1233066
Link: http://search.proquest.com/docview/1314327816/?pq-origsite=primo
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title: Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction.
format: Article
creator:
  • Rosenzweig, Rina
  • Moradi, Shoeib
  • Zarrine-Afsar, Arash
  • Glover, John R
  • Kay, Lewis E
subjects:
  • Adenosine Triphosphatases–Chemistry
  • Adenosine Triphosphate–Genetics
  • Bacterial Proteins–Chemistry
  • Heat-Shock Proteins–Metabolism
  • Hydrolysis–Chemistry
  • Models, Chemical–Chemistry
  • Mutation–Genetics
  • Nuclear Magnetic Resonance, Biomolecular–Genetics
  • Protein Interaction Domains and Motifs–Genetics
  • Protein Interaction Maps–Genetics
  • Protein Multimerization–Genetics
  • Protein Refolding–Genetics
  • Protein Structure, Tertiary–Genetics
  • Protein Transport–Genetics
  • Thermus Thermophilus–Genetics
  • Bacterial Proteins
  • Grpe Protein, Bacteria
  • Heat-Shock Proteins
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
ispartof: Science (New York, N.Y.), March 1, 2013, Vol.339(6123), pp.1080-1083
description: The excessive accumulation of misfolded protein aggregates can overwhelm the cell's "quality control" machinery, leading to cell death. The yeast Hsp104 protein and its bacterial homolog ClpB are molecular chaperones that can "rescue" aggregated proteins by coupling the force generated from adenosine triphosphate hydrolysis to the progressive unfolding and threading of extended polypeptide segments through axial channels in these large molecular machines. Unfolded polypeptides emerging from the channel are refolded with the aid of a second chaperone system, DnaK/DnaJ/GrpE. DnaK also plays an important role in bringing regions of polypeptides within aggregates to ClpB to begin the solubilization process. Rosenzweig et al. (p. 1080, published online 7 February; see the Perspective by Saibil) describe a nuclear magnetic resonance-derived structure of the ClpB-DnaK complex, and verified it through mutagenesis and functional assays. The work clarifies the roles of each of the molecular players in the disaggregation reaction and provides a structural basis for the DnaK-ClpB interaction. [PUBLICATION ] HSP-100 protein machines, such as ClpB, play an essential role in reactivating protein aggregates that can otherwise be lethal to cells. Although the players involved are known, including the DnaK/DnaJ/GrpE chaperone system in bacteria, details of the molecular interactions are not well understood. Using methyl-transverse relaxation-optimized nuclear magnetic resonance spectroscopy, we present an atomic-resolution model for the ClpB-DnaK complex, which we verified by mutagenesis and functional assays. ClpB and GrpE compete for binding to the DnaK nucleotide binding domain, with GrpE binding inhibiting disaggregation. DnaK, in turn, plays a dual role in both disaggregation and subsequent refolding of polypeptide chains as they emerge from the aggregate. On the basis of a combined structural-biochemical analysis, we propose a model for the mechanism of protein aggregate reactivation by ClpB. [PUBLICATION ]
language: eng
source:
identifier: E-ISSN: 1095-9203 ; DOI: 10.1126/science.1233066
fulltext: fulltext
issn:
  • 10959203
  • 1095-9203
url: Link


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titleUnraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction.
creatorRosenzweig, Rina ; Moradi, Shoeib ; Zarrine-Afsar, Arash ; Glover, John R ; Kay, Lewis E
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ispartofScience (New York, N.Y.), March 1, 2013, Vol.339(6123), pp.1080-1083
identifierE-ISSN: 1095-9203 ; DOI: 10.1126/science.1233066
subjectAdenosine Triphosphatases–Chemistry ; Adenosine Triphosphate–Genetics ; Bacterial Proteins–Chemistry ; Heat-Shock Proteins–Metabolism ; Hydrolysis–Chemistry ; Models, Chemical–Chemistry ; Mutation–Genetics ; Nuclear Magnetic Resonance, Biomolecular–Genetics ; Protein Interaction Domains and Motifs–Genetics ; Protein Interaction Maps–Genetics ; Protein Multimerization–Genetics ; Protein Refolding–Genetics ; Protein Structure, Tertiary–Genetics ; Protein Transport–Genetics ; Thermus Thermophilus–Genetics ; Bacterial Proteins ; Grpe Protein, Bacteria ; Heat-Shock Proteins ; Adenosine Triphosphate ; Adenosine Triphosphatases
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descriptionThe excessive accumulation of misfolded protein aggregates can overwhelm the cell's "quality control" machinery, leading to cell death. The yeast Hsp104 protein and its bacterial homolog ClpB are molecular chaperones that can "rescue" aggregated proteins by coupling the force generated from adenosine triphosphate hydrolysis to the progressive unfolding and threading of extended polypeptide segments through axial channels in these large molecular machines. Unfolded polypeptides emerging from the channel are refolded with the aid of a second chaperone system, DnaK/DnaJ/GrpE. DnaK also plays an important role in bringing regions of polypeptides within aggregates to ClpB to begin the solubilization process. Rosenzweig et al. (p. 1080, published online 7 February; see the Perspective by Saibil) describe a nuclear magnetic resonance-derived structure of the ClpB-DnaK complex, and verified it through mutagenesis and functional assays. The work clarifies the roles of each of the molecular players in the disaggregation reaction and provides a structural basis for the DnaK-ClpB interaction. [PUBLICATION ] HSP-100 protein machines, such as ClpB, play an essential role in reactivating protein aggregates that can otherwise be lethal to cells. Although the players involved are known, including the DnaK/DnaJ/GrpE chaperone system in bacteria, details of the molecular interactions are not well understood. Using methyl-transverse relaxation-optimized nuclear magnetic resonance spectroscopy, we present an atomic-resolution model for the ClpB-DnaK complex, which we verified by mutagenesis and functional assays. ClpB and GrpE compete for binding to the DnaK nucleotide binding domain, with GrpE binding inhibiting disaggregation. DnaK, in turn, plays a dual role in both disaggregation and subsequent refolding of polypeptide chains as they emerge from the aggregate. On the basis of a combined structural-biochemical analysis, we propose a model for the mechanism of protein aggregate reactivation by ClpB. [PUBLICATION ]
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titleUnraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction.
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