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Nat Commun. 2018 May 3;9(1):1781. doi: 10.1038/s41467-018-04203-x.

Hsp90 shapes protein and RNA evolution to balance trade-offs between protein stability and aggregation.

Author information

1
Department of Biology, Stanford University, Stanford, CA, 94305, USA.
2
Institute for Integrative Systems Biology (I2SysBio), Universitat de Valencia-CSIC, 46980, Valencia, Spain.
3
Department of Biochemistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
4
Department of Microbiology and Immunology, UCSF, San Francisco, CA, 94131, USA.
5
Laboratory of Virology and Infectious Diseases, Rockefeller University, Rockefeller University, New York, NY, 10065, USA.
6
Department of Microbiology and Immunology, UCSF, San Francisco, CA, 94131, USA. raul.andino@ucsf.edu.
7
Department of Biology, Stanford University, Stanford, CA, 94305, USA. jfrydman@stanford.edu.

Abstract

Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones can influence protein evolution, we examined the effect of reduced activity of the chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets evolutionary trade-offs between protein stability and aggregation. Lower chaperone levels favor variants of reduced hydrophobicity and protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize competing constraints posed by protein stability, aggregation propensity, and translation rate on successful protein biogenesis.

PMID:
29725062
PMCID:
PMC5934419
DOI:
10.1038/s41467-018-04203-x
[Indexed for MEDLINE]
Free PMC Article

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