UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2018-07-23

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Ecology and Evolutionary Biology | Genetic Phenomena

Abstract

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. Collectively, our experiments have identified eight new sensitizing conditions for Lys63 and uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

Keywords

Deep mutational scanning, Evolution, Ubiquitin

Rights and Permissions

Copyright © 2018. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

DOI of Published Version

10.1242/bio.036103

Source

Biol Open. 2018 Jul 23;7(7). pii: 7/7/bio036103. doi: 10.1242/bio.036103. Link to article on publisher's site

Journal/Book/Conference Title

Biology open

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

30037883

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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