Abstract
Determining the forces that conserve amino acid positions in proteins across species is a fundamental pursuit of molecular evolution. Evolutionary conservation is driven by either a protein's function or its thermodynamic stability. Highly conserved histone proteins offer a platform to evaluate these driving forces. While the conservation of histone H3 and H4 “tail” domains and surface residues are driven by functional importance, the driving force behind the conservation of buried histone residues has not been examined. Using a computational approach, we determined the thermodynamically preferred amino acids at each buried position in H3 and H4. In agreement with what is normally observed in proteins, we find a significant correlation between thermodynamic stability and evolutionary conservation in the buried residues in H4. In striking contrast, we find that thermodynamic stability of buried H3 residues does not correlate with evolutionary conservation. Given that these H3 residues are not post-translationally modified and only regulate H3-H3 and H3-H4 stabilizing interactions, our data imply an unknown function responsible for driving conservation of these buried H3 residues.
Highlights
In eukaryotes, histone and non-histone proteins package genomic DNA into higher order chromatin structures
To test the hypothesis that thermodynamic stability drives evolutionary conservation of buried and interface residues in H3 and H4, we calculated the energetic consequences of mutating each of these residues
We looked at residues in the buried core domains of histone proteins H3 and H4, which have no known function other than maintaining the threedimensional structure of the protein
Summary
Histone and non-histone proteins package genomic DNA into higher order chromatin structures. These higher order structures control the accessibility of genomic DNA to various cellular machineries that perform transcription, replication, repair and recombination. The histone octamer comprises of two copies of each of the four histone proteins: H2A, H2B, H3, and H4. (H3-H4) forms a stable tetramer, where two H3-H4 dimers are arranged symmetrically across an interface formed by adjacent H3 molecules (H3,H39; Figure S1A, B). The buried region of the histone octamer can be identified as either the buried residues of the dimers, or the residues that form the interfaces between the dimers while forming the tetramer and octamer
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