Protein evolution. Pervasive degeneracy and epistasis in a protein-protein interface
- PMID: 25657251
- DOI: 10.1126/science.1257360
Protein evolution. Pervasive degeneracy and epistasis in a protein-protein interface
Abstract
Mapping protein sequence space is a difficult problem that necessitates the analysis of 20(N) combinations for sequences of length N. We systematically mapped the sequence space of four key residues in the Escherichia coli protein kinase PhoQ that drive recognition of its substrate PhoP. We generated a library containing all 160,000 variants of PhoQ at these positions and used a two-step selection coupled to next-generation sequencing to identify 1659 functional variants. Our results reveal extensive degeneracy in the PhoQ-PhoP interface and epistasis, with the effect of individual substitutions often highly dependent on context. Together, epistasis and the genetic code create a pattern of connectivity of functional variants in sequence space that likely constrains PhoQ evolution. Consequently, the diversity of PhoQ orthologs is substantially lower than that of functional PhoQ variants.
Copyright © 2015, American Association for the Advancement of Science.
Similar articles
-
The Standard Genetic Code Facilitates Exploration of the Space of Functional Nucleotide Sequences.J Mol Evol. 2018 Jul;86(6):325-339. doi: 10.1007/s00239-018-9852-x. Epub 2018 Jun 29. J Mol Evol. 2018. PMID: 29959476
-
The small membrane protein MgrB regulates PhoQ bifunctionality to control PhoP target gene expression dynamics.Mol Microbiol. 2016 Nov;102(3):430-445. doi: 10.1111/mmi.13471. Epub 2016 Aug 25. Mol Microbiol. 2016. PMID: 27447896
-
Isolation and molecular characterization of the locked-on mutant of Mg2+ sensor PhoQ in Escherichia coli.Biosci Biotechnol Biochem. 2005 Jul;69(7):1281-7. doi: 10.1271/bbb.69.1281. Biosci Biotechnol Biochem. 2005. PMID: 16041131
-
The early evolution of the genetic code.Cell. 2000 Jun 9;101(6):569-72. doi: 10.1016/s0092-8674(00)80866-1. Cell. 2000. PMID: 10892641 Review. No abstract available.
-
Unnatural nucleotide sequences in biopharmaceutics.Adv Pharmacol. 1996;35:321-47. doi: 10.1016/s1054-3589(08)60280-x. Adv Pharmacol. 1996. PMID: 8920210 Review. No abstract available.
Cited by
-
Epistasis facilitates functional evolution in an ancient transcription factor.Elife. 2024 May 20;12:RP88737. doi: 10.7554/eLife.88737. Elife. 2024. PMID: 38767330 Free PMC article.
-
Kinesin-7 CENP-E in tumorigenesis: Chromosome instability, spindle assembly checkpoint, and applications.Front Mol Biosci. 2024 Mar 15;11:1366113. doi: 10.3389/fmolb.2024.1366113. eCollection 2024. Front Mol Biosci. 2024. PMID: 38560520 Free PMC article. Review.
-
Mechanistic causes of sign epistasis and its applications.Front Genet. 2024 Feb 28;15:1366917. doi: 10.3389/fgene.2024.1366917. eCollection 2024. Front Genet. 2024. PMID: 38482385 Free PMC article. Review.
-
Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.bioRxiv [Preprint]. 2024 Mar 26:2024.02.23.581840. doi: 10.1101/2024.02.23.581840. bioRxiv. 2024. PMID: 38464075 Free PMC article. Preprint.
-
Evolution shapes interaction patterns for epistasis and specific protein binding in a two-component signaling system.Commun Chem. 2024 Jan 17;7(1):13. doi: 10.1038/s42004-024-01098-2. Commun Chem. 2024. PMID: 38233668 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases