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

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.

Universal Constraints on Protein Evolution in the Long-Term Evolution Experiment with Escherichia coli

“…Here, I report evidence that purifying selection in the LTEE reflects a universal constraint on protein evolution found across the tree of life, namely that highly abundant and highly interacting proteins evolve slowly ( Fraser et al 2002 ; Hahn et al 2004 ; Drummond et al 2005 ; Hahn and Kern 2005 ; Drummond and Wilke 2008 ; Alvarez-Ponce et al 2017 ). Despite the universality and simplicity of this pattern of purifying selection, its proximate causes continue to be debated ( Plata et al 2010 ; Plata and Vitkup 2018 ; Razban 2019 ; Usmanova et al 2021 ). A number of compelling hypotheses have been proposed, but consensus has not been reached.…”

Purifying selection enduringly acts on the sequence evolution of highly expressed proteins in Escherichia coli

“…These findings are consistent with recent studies indicating that empirical data measuring protein stability, protein aggregation, and protein stickiness do not support the considerable impact of these frequently suggested mechanisms on the E–R anticorrelation for macroevolution (Plata et al . 2010; Plata and Vitkup 2018; Razban 2019; Usmanova et al . 2021).…”

“…The copyright holder for this preprint this version posted March 2, 2022. ; https://doi.org/10.1101/2022.03.02.482674 doi: bioRxiv preprint (2019) reported that the purifying selection for protein sequences within species is much weaker than that between species, suggesting a cautionary note for the applicability of the E-R anticorrelation in relatively recent evolution among bacteria. In addition, recent studies have also pointed out the inconsistency between diverse empirical data across multiple organisms and the predictions from the frequently suggested possible mechanisms explaining the E-R anticorrelation (Plata et al 2010;Plata and Vitkup 2018;Razban 2019;Usmanova et al 2021). For instance, recent genome-scale data empirically measuring protein stability, protein aggregation, and protein stickiness do not support the considerable extent of selection against protein misfolding or protein misinteraction for highly expressed proteins in Escherichia coli (Usmanova et al 2021).…”

“…2001). The underlying mechanism of the E–R anticorrelation remains unclear (Usmanova et al . 2021) but can be explained by several purifying selections, such as the selection against mistranslation and protein misfolding (Akashi 1994; Drummond et al .…”

Targeting the ‘garbage-bin’ to fight cancer: HDAC6 inhibitor WT161 has an anti-tumor effect on osteosarcoma and synergistically interacts with 5-FU

“…Accordingly, the protein molecules 'stick' with each other. Protein aggregation may also be a consequence of protein hyperphosphorylation, self-catalytic conformational conversion, or genetic mutations leading to an unstable protein [3][4][5][6][7][8].…”