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

Autor:	Jaafari H; Center for Theoretical Biophysics, Rice University, Houston, TX 77005.; Applied Physics Graduate Program, Smalley-Curl Institute, Rice University, Houston, TX 77005.; Department of Chemistry, Rice University, Houston, TX 77005., Bueno C; Center for Theoretical Biophysics, Rice University, Houston, TX 77005., Schafer NP; Center for Theoretical Biophysics, Rice University, Houston, TX 77005., Martin J; Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080., Morcos F; Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080.; Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080.; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080., Wolynes PG; Center for Theoretical Biophysics, Rice University, Houston, TX 77005.; Department of Chemistry, Rice University, Houston, TX 77005.; Department of Physics and Astronomy, Rice University, Houston, TX 77005.; Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 21; Vol. 121 (21), pp. e2322428121. Date of Electronic Publication: 2024 May 13.
DOI:	10.1073/pnas.2322428121
Abstrakt:	Protein 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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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