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The Relationship between the Misfolding Avoidance Hypothesis and Protein Evolutionary Rates in the Light of Empirical Evidence.

Authors
  • Usmanova, Dinara R1
  • Plata, Germán1, 2
  • Vitkup, Dennis1, 3
  • 1 Department of Systems Biology, Columbia University, New York, NY, USA.
  • 2 Elanco Animal Health, Greenfield, IN, USA.
  • 3 Department of Biomedical Informatics, Columbia University, New York, NY, USA.
Type
Published Article
Journal
Genome Biology and Evolution
Publisher
Oxford University Press
Publication Date
Feb 03, 2021
Volume
13
Issue
2
Identifiers
DOI: 10.1093/gbe/evab006
PMID: 33432359
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

For more than a decade, the misfolding avoidance hypothesis (MAH) and related theories have dominated evolutionary discussions aimed at explaining the variance of the molecular clock across cellular proteins. In this study, we use various experimental data to further investigate the consistency of the MAH predictions with empirical evidence. We also critically discuss experimental results that motivated the MAH development and that are often viewed as evidence of its major contribution to the variability of protein evolutionary rates. We demonstrate, in Escherichia coli and Homo sapiens, the lack of a substantial negative correlation between protein evolutionary rates and Gibbs free energies of unfolding, a direct measure of protein stability. We then analyze multiple new genome-scale data sets characterizing protein aggregation and interaction propensities, the properties that are likely optimized in evolution to alleviate deleterious effects associated with toxic protein misfolding and misinteractions. Our results demonstrate that the propensity of proteins to aggregate, the fraction of charged amino acids, and protein stickiness do correlate with protein abundances. Nevertheless, across multiple organisms and various data sets we do not observe substantial correlations between proteins' aggregation- and stability-related properties and evolutionary rates. Therefore, diverse empirical data support the conclusion that the MAH and similar hypotheses do not play a major role in mediating a strong negative correlation between protein expression and the molecular clock, and thus in explaining the variability of evolutionary rates across cellular proteins. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

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