The physical and evolutionary energy landscapes of devolved protein sequences corresponding to pseudogenes

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dc.citation.articleNumbere2322428121en_US
dc.citation.issueNumber21en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber121en_US
dc.contributor.authorJaafari, Hanaen_US
dc.contributor.authorBueno, Carlosen_US
dc.contributor.authorSchafer, Nicholas P.en_US
dc.contributor.authorMartin, Jonathanen_US
dc.contributor.authorMorcos, Farucken_US
dc.contributor.authorWolynes, Peter G.en_US
dc.contributor.orgCenter for Theoretical Biophysicsen_US
dc.date.accessioned2024-11-04T16:25:12Zen_US
dc.date.available2024-11-04T16:25:12Zen_US
dc.date.issued2024en_US
dc.description.abstractProtein evolution is guided by structural, functional, and dynamical constraints ensuring organismal viability. Pseudogenes are genomic sequences identified in many eukaryotes that lack translational activity due to sequence degradation and thus over time have undergone “devolution.” Previously pseudogenized genes sometimes regain their protein-coding function, suggesting they may still encode robust folding energy landscapes despite multiple mutations. We study both the physical folding landscapes of protein sequences corresponding to human pseudogenes using the Associative Memory, Water Mediated, Structure and Energy Model, and the evolutionary energy landscapes obtained using direct coupling analysis (DCA) on their parent protein families. We found that generally mutations that have occurred in pseudogene sequences have disrupted their native global network of stabilizing residue interactions, making it harder for them to fold if they were translated. In some cases, however, energetic frustration has apparently decreased when the functional constraints were removed. We analyzed this unexpected situation for Cyclophilin A, Profilin-1, and Small Ubiquitin-like Modifier 2 Protein. Our analysis reveals that when such mutations in the pseudogene ultimately stabilize folding, at the same time, they likely alter the pseudogenes’ former biological activity, as estimated by DCA. We localize most of these stabilizing mutations generally to normally frustrated regions required for binding to other partners.en_US
dc.identifier.citationJaafari, H., Bueno, C., Schafer, N. P., Martin, J., Morcos, F., & Wolynes, P. G. (2024). The physical and evolutionary energy landscapes of devolved protein sequences corresponding to pseudogenes. Proceedings of the National Academy of Sciences, 121(21), e2322428121. https://doi.org/10.1073/pnas.2322428121en_US
dc.identifier.digitaljaafari-et-al-2024en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2322428121en_US
dc.identifier.urihttps://hdl.handle.net/1911/117995en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleThe physical and evolutionary energy landscapes of devolved protein sequences corresponding to pseudogenesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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