Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme
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Yang, Gloria; Anderson, Dave W.; Baier, Florian; Dohmen , Elias; Hong, Nansook; Carr, Paul D; Kamerlin, Shina CL; Jackson, Colin; Bornberg-Bauer, Erich; Tokuriki, Nobuhiko
Description
Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral...[Show more]
dc.contributor.author | Yang, Gloria | |
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dc.contributor.author | Anderson, Dave W. | |
dc.contributor.author | Baier, Florian | |
dc.contributor.author | Dohmen , Elias | |
dc.contributor.author | Hong, Nansook | |
dc.contributor.author | Carr, Paul D | |
dc.contributor.author | Kamerlin, Shina CL | |
dc.contributor.author | Jackson, Colin | |
dc.contributor.author | Bornberg-Bauer, Erich | |
dc.contributor.author | Tokuriki, Nobuhiko | |
dc.date.accessioned | 2020-09-17T04:33:00Z | |
dc.identifier.issn | 1552-4450 | |
dc.identifier.uri | http://hdl.handle.net/1885/210606 | |
dc.description.abstract | Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral dihydrocoumarin hydrolase. In-depth analyses of the adaptive landscapes encompassing this evolutionary transition revealed that the mutations form a complex interaction network, defined in part by higher-order epistasis, that constrained the adaptive pathways available. By also characterizing the adaptive landscapes in terms of their functional activities towards three additional organophosphate substrates, we reveal that subtle differences in the polarity of the substrate substituents drastically alter the network of epistatic interactions. Our work suggests that the mutations function collectively to enable substrate recognition via subtle structural repositioning. | |
dc.description.sponsorship | N.T. and E.B.-B. thank the Human Frontier Science Program (HFSP) for support via research grant RGP0006/2013. N.T. acknowledges support by the Natural Sciences and Engineering Research Council of Canada (NSERC) via discovery grants RGPIN 418262-12 and RGPIN 2017-04909. N.T. is a CIHR new investigator and a Michael Smith Foundation of Health Research (MSFHR) career investigator. S.C.L.K. thanks the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellowships 2013.0124 and 2018.0140) and the Swedish National Infrastructure for Computing (SNIC). D.W.A. thanks NSERC and the MSFHR for post-doctoral support. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | Nature Publishing Group | |
dc.rights | © The Author(s), under exclusive licence to Springer Nature America, Inc. 2019 | |
dc.source | Nature Chemical Biology | |
dc.title | Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 15 | |
dc.date.issued | 2019 | |
local.identifier.absfor | 030403 - Characterisation of Biological Macromolecules | |
local.identifier.ariespublication | u3102795xPUB5391 | |
local.publisher.url | http://www.nature.com/nchembio/ | |
local.type.status | Published Version | |
local.contributor.affiliation | Yang, Gloria, University of British Columbia | |
local.contributor.affiliation | Anderson, Dave W., University of British Columbia | |
local.contributor.affiliation | Baier, Florian, University of British Columbia | |
local.contributor.affiliation | Dohmen , Elias, Westfälische Wilhelms University | |
local.contributor.affiliation | Hong, Nansook, College of Science, ANU | |
local.contributor.affiliation | Carr, Paul D, College of Science, ANU | |
local.contributor.affiliation | Kamerlin, Shina CL, Uppsala University | |
local.contributor.affiliation | Jackson, Colin, College of Science, ANU | |
local.contributor.affiliation | Bornberg-Bauer, Erich, Westfalische Wilhems-Universitat Munster | |
local.contributor.affiliation | Tokuriki, Nobuhiko, University of British Columbia | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 11 | |
local.bibliographicCitation.startpage | 1120 | |
local.bibliographicCitation.lastpage | 1128 | |
local.identifier.doi | 10.1038/s41589-019-0386-3 | |
local.identifier.absseo | 970103 - Expanding Knowledge in the Chemical Sciences | |
dc.date.updated | 2020-06-23T00:55:00Z | |
local.identifier.scopusID | 2-s2.0-85073657282 | |
Collections | ANU Research Publications |
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