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

Sebastian Pechmann,Raul Andino,Ashley Acevedo,Judith Frydman,Ron Geller

doi:10.1038/s41467-018-04203-x

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.

Highlights

Acquisition of mutations is central to evolution; the detrimental effects of most mutations on protein folding and stability limit protein evolvability
Our results reveal that a key eukaryotic chaperone influences the sequence landscape of its client protein at both the protein and RNA levels, mediating the competing constraints posed by protein stability, aggregation propensity, and translation rate
To gain a better understanding of how Hsp[90] shapes virus evolution, we examined the diversity of poliovirus populations at unprecedented resolution using recent technological advancements in ultra-deep sequencing that provide a detailed description of the viral population mutation composition[24]

Summary

Introduction

Acquisition of mutations is central to evolution; the detrimental effects of most mutations on protein folding and stability limit protein evolvability. 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. As viral proteins meet folding and stability challenges akin to those of host proteins, and utilize the host-cell translation and folding machineries, viruses offer a unique opportunity to examine how chaperones shape protein evolution. The high diversity and evolutionary capacity of poliovirus, together with the fact that it harbors only a single protein that requires Hsp[90] for folding, the capsid precursor P1, provide an ideal system to examine the role of Hsp[90] in protein evolution (Fig. 1a). Our results reveal that a key eukaryotic chaperone influences the sequence landscape of its client protein at both the protein and RNA levels, mediating the competing constraints posed by protein stability, aggregation propensity, and translation rate

Methods

Results

Conclusion