Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis

Ortlund, Eric A.; Bridgham, Jamie T.; Redinbo, Matthew R.

doi:10.1126/science.1142819

Cited by 391 publications

(456 citation statements)

References 32 publications

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“…For the same given set of mutations, it may be that one temporal order of mutations is evolutionarily favoured because it entails a monotonic increase in fitness, whereas another order of mutations is disfavoured because it involves an intermediate step that decreases fitness. Several studies have demonstrated this type of epistatic behaviour in proteins and its constraints on evolutionary pathways [42,53,300,[395][396][397][398]. For instance, experiments on adenylate kinase indicate that a double mutant with higher stability can only be obtained via one mutation path [300].…”

Section: Epistasis and Co-evolution Of Interacting Amino Acid Residuesmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

220

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Epistasis and Co-evolution Of Interacting Amino Acid Residuesmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

220

207

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“…In this case, enhancement of nGRE-binding ability in the GR lineage and the loss of nGRE-binding ability in the MR and AncSR3 lineages were critical for development of divergent DNA specificity. Both computational and directed evolution studies have implicated epistasis as a primary factor in molecular evolution (34,35), and studies of historical protein divergence have established a major role for epistasis in specific cases (28,(36)(37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

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

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Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

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“…A mutation that is beneficial at the time of its introduction may confer its beneficial effect only in the presence of other potentiating or permissive mutations (1)(2)(3)(4)(5)(6)(7)(8)(9). Thus, the fate of a mutation arising in a population may be contingent on previous mutations (10)(11)(12)(13).…”

mentioning

confidence: 99%

Contingency and entrenchment in protein evolution under purifying selection

Shah

McCandlish

Plotkin

2015

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

182

236

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The phenotypic effect of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations and shape the patterns of protein divergence across species. Whereas epistasis between adaptive substitutions has been studied extensively, relatively little is known about epistasis under purifying selection. Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution. Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis. In particular, the mutations that fix are contingent on previous substitutions: Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time. Our results imply that, even under purifying selection, protein sequence evolution is often contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the ancestral background.intragenic epistasis | coevolution | near neutrality | protein stability W hether a heritable mutation is advantageous or deleterious to an organism often depends on the evolutionary history of the population. A mutation that is beneficial at the time of its introduction may confer its beneficial effect only in the presence of other potentiating or permissive mutations (1-9). Thus, the fate of a mutation arising in a population may be contingent on previous mutations (10-13). Conversely, once a mutation has fixed in a population, the mutation becomes part of the genetic background onto which subsequent modifications are introduced. Because the beneficial effects of the subsequent modifications may depend on the focal mutation, as time passes reversion of the focal mutation may become increasingly deleterious, leading to a type of evolutionary conservatism, or entrenchment (14-18).In the context of protein evolution, the effects of contingency and entrenchment are most easily studied by considering a sequence of single amino acid changes (19) that extends both forward and backward in time from some focal substitution. To assess the roles of contingency and entrenchment we can study the degree to which each focal substitution was facilitated by previous substitutions, and the degree to which the focal substitution influences the subsequent course of evolution (Fig. 1A).Dependencies within a sequence of substitutions are closely connected to the concept of epistasis-that is, the idea that the phenotypic effect of a mutation at a particular genetic site may depend on the genetic background in which it arises (20-24). In the absence of epistasis, a mutation has the same effect ...

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Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis

Cited by 391 publications

References 32 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Contingency and entrenchment in protein evolution under purifying selection

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