Binding constraints on the evolution of enzymes and signalling proteins: the important role of negative pleiotropy

Liberles, David A.; Tisdell, Makayla D. M.; Grahnen, Johan A.

doi:10.1098/rspb.2010.2637

Cited by 29 publications

(26 citation statements)

References 36 publications

(38 reference statements)

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“…Selection against misfolding can explain part of the correlation (24,25), where the assumption is that toxicity of misfolded proteins is proportional to their abundance. Our results support the notion that avoidance of promiscuous interactions, or negative pleiotropy (32), represents an additional mechanistic explanation (Fig. 4B).…”

Section: Nonfunctional Interactions Might Contribute To the Differentialsupporting

confidence: 80%

Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

Levy

Teichmann

2012

Proc. Natl. Acad. Sci. U.S.A.

165

222

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In living cells, functional protein-protein interactions compete with a much larger number of nonfunctional, or promiscuous, interactions. Several cellular properties contribute to avoiding unwanted protein interactions, including regulation of gene expression, cellular compartmentalization, and high specificity and affinity of functional interactions. Here we investigate whether other mechanisms exist that shape the sequence and structure of proteins to favor their correct assembly into functional protein complexes. To examine this question, we project evolutionary and cellular abundance information onto 397, 196, and 631 proteins of known 3D structure from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, respectively. On the basis of amino acid frequencies in interface patches versus the solvent-accessible protein surface, we define a propensity or "stickiness" scale for each of the 20 amino acids. We find that the propensity to interact in a nonspecific manner is inversely correlated with abundance. In other words, high abundance proteins have less sticky surfaces. We also find that stickiness constrains protein evolution, whereby residues in sticky surface patches are more conserved than those found in nonsticky patches. Finally, we find that the constraint imposed by stickiness on protein divergence is proportional to protein abundance, which provides mechanistic insights into the correlation between protein conservation and protein abundance. Overall, the avoidance of nonfunctional interactions significantly influences the physico-chemical and evolutionary properties of proteins. Remarkably, the effects observed are consistently larger in E. coli and S. cerevisiae than in H. sapiens, suggesting that promiscuous protein-protein interactions may be freer to accumulate in the human lineage.promiscuity | protein structure | interaction potential

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Section: Nonfunctional Interactions Might Contribute To the Differentialsupporting

confidence: 80%

Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

Levy

Teichmann

2012

Proc. Natl. Acad. Sci. U.S.A.

165

222

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“…Although our computer simulation focused on the role of misinteraction avoidance in constraining the evolution of proteins with presumably unchanged functions, the same constraint can also hinder neofunctionalization in protein evolution; therefore, a mutation conferring a new function may be unacceptable, because it compromises misinteraction avoidance (50). It is possible that the E-R anticorrelation reflects reductions of both neutral substitution rates and advantageous substitution rates in highly expressed proteins.…”

Section: Discussionmentioning

confidence: 99%

Protein misinteraction avoidance causes highly expressed proteins to evolve slowly

Yang

Liao

Zhuang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

167

175

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The tempo and mode of protein evolution have been central questions in biology. Genomic data have shown a strong influence of the expression level of a protein on its rate of sequence evolution (E-R anticorrelation), which is currently explained by the protein misfolding avoidance hypothesis. Here, we show that this hypothesis does not fully explain the E-R anticorrelation, especially for protein surface residues. We propose that natural selection against protein–protein misinteraction, which wastes functional molecules and is potentially toxic, constrains the evolution of surface residues. Because highly expressed proteins are under stronger pressures to avoid misinteraction, surface residues are expected to show an E-R anticorrelation. Our molecular-level evolutionary simulation and yeast genomic analysis confirm multiple predictions of the hypothesis. These findings show a pluralistic origin of the E-R anticorrelation and reveal the role of protein misinteraction, an inherent property of complex cellular systems, in constraining protein evolution.

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“…Ultimately, to understand patterns like this we would need to know how β-lactamase interacts with different antibiotics on an atomic scale, and how different β-lactamase mutants differ in this interaction, as well as in other properties, such as their thermodynamic stability. For other proteins, a combination of experimental and computational work is beginning to facilitate understanding of how biophysical and chemical properties like these can affect the molecular evolution of proteins [78][79][80][81][82][83][84][85]. But even though β-lactamases are extremely well-studied biochemically and evolutionarily, their interactions with antibiotics are still insufficiently understood.…”

Section: E)mentioning

confidence: 99%

Phenotypic Constraints and Phenotypic Hitchhiking in a Promiscuous Enzyme

Wagner

Weikert

2012

TOEVOLJ

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Covarying phenotypic traits can limit natural selection's ability to modify these traits. Most evolutionary studies on trait covariation use the comparative method to study complex traits of multicellular organisms. Simpler traits have the advantage of being amenable to experimental evolution. Here we study such a simple molecular system, the TEM-1 beta-lactamase protein, a promiscuous enzyme that hydrolyses antibiotics, and thus confers antibiotic resistance to bacteria. We mutagenized large populations of TEM-1, and selected in these populations for activity on the four different antibiotics ampicillin, carbenicillin, oxacillin, and penicillin G. While mutagenesis alone lead to highly correlated changes in enzyme activity on the four antibiotics, subsequent selection was able to modify this activity covariation substantially, and even lead to uncorrelated activities. We found that selection on one antibiotic A may be more effective in increasing activity on another antibiotic B then selection on antibiotic B itself. We call this phenomenon phenotypic hitchhiking. It can be readily explained through quantitative genetic theory as a consequence of differing variances in covarying traits. It may help engineer macromolecules with desirable properties through directed evolution. Our analysis is a first step towards systematic analysis of trait covariation in experimental molecular systems. It shows that selection may readily modify the phenotypic constraints that limit its efficacy. Abstract: Covarying phenotypic traits can limit natural selection's ability to modify these traits. Most evolutionary studies on trait covariation use the comparative method to study complex traits of multicellular organisms. Simpler traits have the advantage of being amenable to experimental evolution. Here we study such a simple molecular system, the TEM-1 beta-lactamase protein, a promiscuous enzyme that hydrolyses antibiotics, and thus confers antibiotic resistance to bacteria. We mutagenized large populations of TEM-1, and selected in these populations for activity on the four different antibiotics ampicillin, carbenicillin, oxacillin, and penicillin G. While mutagenesis alone lead to highly correlated changes in enzyme activity on the four antibiotics, subsequent selection was able to modify this activity covariation substantially, and even lead to uncorrelated activities. We found that selection on one antibiotic A may be more effective in increasing activity on another antibiotic B then selection on antibiotic B itself. We call this phenomenon phenotypic hitchhiking. It can be readily explained through quantitative genetic theory as a consequence of differing variances in covarying traits. It may help engineer macromolecules with desirable properties through directed evolution. Our analysis is a first step towards systematic analysis of trait covariation in experimental molecular systems. It shows that selection may readily modify the phenotypic constraints that limit its efficacy.

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Binding constraints on the evolution of enzymes and signalling proteins: the important role of negative pleiotropy

Cited by 29 publications

References 36 publications

Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

Protein misinteraction avoidance causes highly expressed proteins to evolve slowly

Phenotypic Constraints and Phenotypic Hitchhiking in a Promiscuous Enzyme

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