Thermodynamic Stability of Histone H3 is a Necessary but not Sufficient Driving Force for its Evolutionary Conservation

Abstract

Determining the forces that drive evolutionary conservation of amino acid sequences of proteins has been a fundamental pursuit of molecular evolution. In the absence of any other function, it is thought that the core domains of proteins are conserved to maintain the thermodynamic stability of the protein. We have sought to test this idea further using the strongly conserved buried core of histone proteins H3 and H4. Consistent with previous notions, we observed a strong correlation between survival fitness in yeast and nucleosome thermodynamic stability. However, in striking contrast to what is normally observed, we find that thermodynamic stability of buried histone H3 residues is not correlated with evolutionary conservation. Thus, H3 is fundamentally different in comparison to many proteins studied to date, including highly conserved proteins like actin, tubulin and histone H4. The discovery of the uniqueness in conservation of H3 goes against the conventional view that buried H3 residues are highly conserved just to maintain the stability of the nucleosome. This discovery thus points to either new additional functions of histone H3 that have not been uncovered or a unique conservation mechanism that goes beyond survival pressure.