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Mol Biol Evol. 2014 Jul;31(7):1641-5. doi: 10.1093/molbev/msu137. Epub 2014 Apr 16.

Signatures of natural selection on mutations of residues with multiple posttranslational modifications.

Author information

1
Center for Evolutionary Medicine and Informatics, Biodesign Institute, Arizona State University.
2
Cell Signaling Technology, Danvers, MA.
3
Center for Evolutionary Medicine and Informatics, Biodesign Institute, Arizona State UniversitySchool of Life Sciences, Arizona State UniversityCenter for Genomic Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia s.kumar@asu.edu.

Abstract

Posttranslational modifications (PTMs) regulate molecular structures and functions of proteins by covalently binding to amino acids. Hundreds of thousands of PTMs have been reported for the human proteome, with multiple PTMs known to affect tens of thousands of lysine (K) residues. Our molecular evolutionary analyses show that K residues with multiple PTMs exhibit greater conservation than those with a single PTM, but the difference is rather small. In contrast, short-term evolutionary trends revealed in an analysis of human population variation exhibited a much larger difference. Lysine residues with three PTMs show 1.8-fold enrichment of Mendelian disease-associated variants when compared with K residues with two PTMs, with the latter showing 1.7-fold enrichment of these variants when compared with the K residues with one PTM. Rare polymorphisms in humans show a similar trend, which suggests much greater negative selection against mutations of K residues with multiple PTMs within population. Conversely, common polymorphisms are overabundant at unmodified K residues and at K residues with fewer PTMs. The observed difference between inter- and intraspecies patterns of purifying selection on residues with PTMs suggests extensive species-specific drifting of PTM positions. These results suggest that the functionality of a protein is likely conserved, without necessarily conserving the PTM positions over evolutionary time.

KEYWORDS:

evolution; posttranslational modification; proteomics

PMID:
24739307
PMCID:
PMC4069621
DOI:
10.1093/molbev/msu137
[Indexed for MEDLINE]
Free PMC Article
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