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Enzyme Evolution An Epistatic Ratchet versus a Smooth Reversible Transition
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2019 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 37, no 4, p. 1133-1147Article in journal (Refereed) Published
Abstract [en]

Evolutionary trajectories are deemed largely irreversible. In a newly diverged protein, reversion of mutations that led to the functional switch typically results in loss of both the new and the ancestral functions. Nonetheless, evolutionary transitions where reversions are viable have also been described. The structural and mechanistic causes of reversion compatibility versus incompatibility therefore remain unclear. We examined two laboratory evolution trajectories of mammalian paraoxonase-1, a lactonase with promiscuous organophosphate hydrolase (OPH) activity. Both trajectories began with the same active-site mutant, His115Trp, which lost the native lactonase activity and acquired higher OPH activity. A neo-functionalization trajectory amplified the promiscuous OPH activity, whereas the re-functionalization trajectory restored the native activity, thus generating a new lactonase that lacks His115. The His115 revertants of these trajectories indicated opposite trends. Revertants of the neo-functionalization trajectory lost both the evolved OPH and the original lactonase activity. Revertants of the trajectory that restored the original lactonase function were, however, fully active. Crystal structures and molecular simulations show that in the newly diverged OPH, the reverted His115 and other catalytic residues are displaced, thus causing loss of both the original and the new activity. In contrast, in the re-functionalization trajectory, reversion compatibility of the original lactonase activity derives from mechanistic versatility whereby multiple residues can fulfill the same task. This versatility enables unique sequence-reversible compositions that are inaccessible when the active site was repurposed toward a new function.

Place, publisher, year, edition, pages
2019. Vol. 37, no 4, p. 1133-1147
National Category
Natural Sciences
Research subject
Biology with specialization in Molecular Biology; Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-407415DOI: 10.1093/molbev/msz298OAI: oai:DiVA.org:uu-407415DiVA, id: diva2:1416561
Conference
3/24/2020
Available from: 2020-03-24 Created: 2020-03-24 Last updated: 2020-03-25
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Publisher's full texthttps://doi.org/10.1093/molbev/msz298

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Liao, QinghuaSzeler, KlaudiaKamerlin, Shina C. Lynn

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Liao, QinghuaSzeler, KlaudiaKamerlin, Shina C. Lynn
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Structural BiologyScience for Life Laboratory, SciLifeLabDepartment of Cell and Molecular BiologyBiochemistry
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Molecular biology and evolution
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