Research

Aiming at increasing our understanding of biological diversity, my research is centered on the interplay between structure and function in protein evolution. Currently, two main foci are prevalent in my research; protein structure evolution and protein pathway evolution.

Within the area of protein structure evolution, our investigations include the superfold topologies and neostructuralization. For the superfolds, we are interested in the question if domains with the same superfold topology are homologous despite high sequence and functional divergence. Our methodology for this project involves a journey back in time. Using the well established concept that structure is more conserved than sequence, we can detect potential remote homologs by their structures. The potential homologs are then clustered based upon structural and sequential similarities. For each potential homolog, the protein family is expanded and the ancestral sequences for each protein family are reconstructed. The structure of last common ancestor for each family, aka the root, is modeled using homology modeling and all models are then clustered together (Figure 1). The ultimate test is whether the root models are closer to each other than the actual structures.

Figure 1. Outline of the remote homology project.

For neostructuralization, we are initially studying the disordered proteins. As mentioned above, protein structure is known to be more conserved than sequence, yet we know that this is not always the case. To gain insights to how common neostructuralization, or fold transitions, are, we are investigation the disordered proteins. The disordered proteins have specific properties, e.g. extreme induced fit and structural flexibility, that can govern neostructuralization among paralogs. This investigation is performed by comparing proteins with experimentally determined the disorder over evolutionary time.

Within the project of protein pathway evolution, we are studying the dopamine and serotonin pathways. As these two parallel pathways share one enzyme and use another duplicated enzyme family extensively, they seem to have co-evolved. We are analyzing how the different families within these pathways have evolved, with regard to phylogenies, gene duplications and functional change.