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Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function
- Source :
- Cell Reports, Vol 15, Iss 3, Pp 588-598 (2016)
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- SummaryTo probe the mechanism of the Hsp90 chaperone that is required for the maturation of many signaling proteins in eukaryotes, we analyzed the effects of all individual amino acid changes in the ATPase domain on yeast growth rate. The sensitivity of a position to mutation was strongly influenced by proximity to the phosphates of ATP, indicating that ATPase-driven conformational changes impose stringent physical constraints on Hsp90. To investigate how these constraints may vary for different clients, we performed biochemical analyses on a panel of Hsp90 mutants spanning the full range of observed fitness effects. We observed distinct effects of nine Hsp90 mutations on activation of v-src and glucocorticoid receptor (GR), indicating that different chaperone mechanisms can be utilized for these clients. These results provide a detailed guide for understanding Hsp90 mechanism and highlight the potential for inhibitors of Hsp90 that target a subset of clients.
- Subjects :
- 0301 basic medicine
Models, Molecular
ATPase
Mutant
Saccharomyces cerevisiae
Computational biology
General Biochemistry, Genetics and Molecular Biology
Article
Conserved sequence
Evolution, Molecular
03 medical and health sciences
0302 clinical medicine
Glucocorticoid receptor
Adenosine Triphosphate
Humans
HSP90 Heat-Shock Proteins
Amino Acids
lcsh:QH301-705.5
Conserved Sequence
Genetics
chemistry.chemical_classification
Adenosine Triphosphatases
biology
Adenine
1. No poverty
biology.organism_classification
Hsp90
Amino acid
030104 developmental biology
chemistry
lcsh:Biology (General)
Chaperone (protein)
Mutation
biology.protein
Genetic Fitness
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 15
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....cc56a534960987bd90328a7607d94e27
- Full Text :
- https://doi.org/10.1016/j.celrep.2016.03.046