Abstract
Conformational and functional flexibility promote protein evolvability. High evolvability allows related proteins to functionally diverge and perhaps to neostructuralize. p53 is a multifunctional protein frequently referred to as the Guardian of the Genome–a hub for e.g. incoming and outgoing signals in apoptosis and DNA repair. p53 has been found to be structurally disordered, an extreme form of conformational flexibility. Here, p53, and its paralogs p63 and p73, were studied for further insights into the evolutionary dynamics of structural disorder, secondary structure, and phosphorylation. This study is focused on the post gene duplication phase for the p53 family in vertebrates, but also visits the origin of the protein family and the early domain loss and gain events. Functional divergence, measured by rapid evolutionary dynamics of protein domains, structural properties, and phosphorylation propensity, is inferred across vertebrate p53 proteins, in p63 and p73 from fish, and between the three paralogs. In particular, structurally disordered regions are redistributed among paralogs, but within clades redistribution of structural disorder also appears to be an ongoing process. Despite its deemed importance as the Guardian of the Genome, p53 is indeed a protein with high evolvability as seen not only in rearranged structural disorder, but also in fluctuating domain sequence signatures among lineages.
Highlights
Proteins are dynamic, with a natural tendency to rearrange their conformational ensembles in response to the local environment [1]
A representative p53 family phylogeny including a selection of species ranging from choanoflagellates to primates was constructed for the p53 DNA binding domain (p53 DBD) (Fig 1A)
Considering that the same four domain combination is recovered in early chordates, this indicates that this four domain cassette was present prior to the emergence of Ecdysozoa including arthropods (Fig 1B)
Summary
With a natural tendency to rearrange their conformational ensembles in response to the local environment [1]. Conformational flexibility is associated with functional promiscuity and together they promote evolvability [2]. Evolvability offers a route to functional and structural divergence among related proteins, allowing related proteins to functionally diversify and perhaps to neostructuralize [3] and could manifest as a fold transition, a domain change, or a change in conformational flexibility. Evolutionary Dynamics of Sequence, Structure, and Phosphorylation in the p53, p63, and p73 Paralogs the interplay between amino acid residues in proteins and the degree of flexibility depends on the nature of the amino acids. Structurally disordered protein regions are conformationally flexible. It follows that if the property of structural disorder is not evolutionarily conserved for homologous sites in a protein family, conformational and functional divergence may be inferred
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