Unraveling the Mechanism of Protein Disaggregation Through a ClpB-DnaK Interaction
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....
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2013-03, Vol.339 (6123), p.1080-1083 |
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| container_title | Science (American Association for the Advancement of Science) |
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| creator | Rosenzweig, Rina Moradi, Shoeib Zarrine-Afsar, Arash Glover, John R. Kay, Lewis E. |
| description | 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. |
| doi_str_mv | 10.1126/science.1233066 |
| format | Article |
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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. 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| subjects | Adenosine triphosphatases Adenosine Triphosphatases - chemistry Adenosine Triphosphatases - genetics Adenosine triphosphate Adenosine Triphosphate - chemistry Adenosine Triphosphate - metabolism Aggregates Bacteria Bacterial Proteins - chemistry Binding sites Biochemistry Cell aggregates Channels Genetic mutation Heat-Shock Proteins - chemistry Heat-Shock Proteins - genetics Hydrolysis Meningioma Models, Chemical Molecular structure Mutation Nuclear magnetic resonance Nuclear Magnetic Resonance, Biomolecular Nucleotides Polypeptides Protein folding Protein Interaction Domains and Motifs Protein Interaction Maps Protein Multimerization Protein Refolding Protein Structure, Tertiary Protein Transport Proteins Quality Control Solubilization Thermus thermophilus Titration |
| title | Unraveling the Mechanism of Protein Disaggregation Through a ClpB-DnaK Interaction |
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