Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Evolutionary Dynamics of Conformational Flexibility

A fundamental assumption in biology is that protein structure is more conserved than protein sequence. This opinion stems from observations of the fold distribution of protein structures present in the protein data bank (PDB), where homologous proteins are found to display the same fold. However, the set of proteins in PDB is not representative of protein sequence space. The predominant experimental method used for the structural characterization of the proteins in PDB is x-ray crystallography. Thus, conformational flexibility is lost and a static snapshot of a protein’s dynamic structure remains. Using structural disorder as a proxy for protein dynamism, it seems that at least 30 % of eukaryotic proteins have dynamic regions, that is, regions with conformational flexibility. Little is known about the conservation of structurally disordered regions, except that they often evolve at an elevated rate compared to the structured regions. Our preliminary results indicate that there are regions that show fast evolutionary dynamics of structural disorder. A feature of structurally disordered proteins is their functional promiscuity; these proteins often interact with many different biomolecules in a signaling fashion. A central tenet of protein structure and function is that a protein’s function is given by its structure. Structurally disordered proteins exist as conformational ensembles and hence, it is intuitive that a functional ensemble would accompany the structural ensemble. The different conformations in the ensemble are rapidly interconverting over a shallow free energy landscape with multiple minima of similarly low stability. In accordance with the extended view of allostery (conformational selection), stabilizing interactions with other biomolecules can drive the population of conformations towards a particular functional conformation. Further, coupling the conformational ensemble free energy landscape to an adaptive fitness landscape for gene/protein function, we are investigating how proteins with conformational and functional ensembles evolve.

Here a study across flaviviruses is presented. Flaviviruses depend on conformational flexibility at many steps in their life cycle and the entire flavivirus proteome contains about 3400 amino acid long polyprotein that is spliced into 11-12 proteins. Therefore full genome studies are feasible. We find support for mutation-driven conformational selection, as amino acid substitutions can increase the rate of divergence of conformational flexibility among different homologous proteins. Some regions are more prone to shift from order to disorder or vice versa and some lineages show rapid shifts from order to disorder. Lineage-specific shift between disorder and order can alter the conformational ensemble for the same protein in different species, causing a subtle functional change. Thus, rapid evolutionary dynamics of structural disorder could be a potential driving force for biological divergence among flaviviruses.

This work was supported by Award Number P20RR016474 from the National Center for Research Resources. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Juan F. Ortiz
Patrick Masterson
Madolyn Macdonald
Vladimir N. Uversky
Jessica Siltberg-Liberles

Department of Molecular Biology
University of Wyoming
Laramie, WY 82071

Ph: 307-766-3181
Fx: 307-766-5098