Repo, Susanna

Structural Bioinformatics Laboratory Department of Biochemistry and Pharmacy Åbo Akademi University Tykistökatu 6, FI-20520 Turku, Finland susanna.repo@abo.fi Arrives: 20 July Departs: 16 August

I completed my Ph.D. at Åbo Akademi University, Turku, Finland, in the lab of Professor Mark S. Johnson. In my thesis, I focused on the three-dimensional structures of proteins, and applied structural bioinformatics tools and phylogenetic analysis in order to study the ligand-binding specificities and functional evolution of proteins from three different protein families: amino acid decarboxylases, biotin-binding proteins and nuclear receptors. This fall I will join the Computational Genomics Research Group as a postdoc at University of California, Berkeley with Dr. Steven Brenner. In my postdoctoral research I will focus on the prediction of protein function with bayesian phylogenomics and investigate sequence data from environmental and medical metagenomics studies.

Dissertation research

Structural bioinformatics is a subdiscipline of bioinformatics, where computational methods for the production, analysis and visualization of the three-dimensional structures of biological macromolecules are developed. The main aim of structural bioinformatics is to apply these tools to elucidate the structure of biological macromolecules and derive knowledge from the structure in order to investigate the function of the macromolecule. In my thesis, the focus was on the three-dimensional structures of proteins, which carry a significant amount of information about the function and the evolutionary history of the protein.

In my thesis work, I investigated the ligand-binding specificities and properties of proteins from three different protein families: amino acid decarboxylases, biotin-binding proteins and nuclear receptors. Even if the main focus of my thesis was on computational methods such as molecular docking and phylogenetic analysis, the three projects also relied on experimental data either produced by our collaborators or derived from the literature.

The amino acid decarboxylases form a large superfamily of proteins with different substrate specificities. In my thesis, an extensive phylogenetic analysis of the superfamily enabled the functional classification of non-annotated decarboxylase sequences. The analysis revealed a previously unknown group of prokaryotic decarboxylase sequences that are more closely related to eukaryotic decarboxylases than to the other bacterial sequences. The predictions were supported by observations from detailed sequence and structural analyses demonstrating the power of phylogenomics in the prediction of protein function even in more distantly related protein families.

Avidin and avidin-related protein 4 (AVR4) are biotin-binding proteins, which are widely exploited in biotechnology. In addition to D-biotin, avidin binds with moderate affinity an azo dye compound called HABA. In my thesis, the binding of avidin and AVR4 to 15 synthetic HABA-derivatives were investigated. The results showed that the two related proteins have clearly different azo-compound binding preferences. Molecular docking studies indicated that the binding preferences were largely due to the conformation of the loop between β-strands 3 and 4, which in avidin is more flexible in comparison with the corresponding loop in AVR4.

The constitutive androstane receptor (CAR) belongs to the nuclear receptor family of transcription factors and acts as a chemical sensor, which mediates the metabolism and elimination of drugs and endogenous compounds. In my thesis, new knowledge on the residues important for ligand recognition by mouse CAR was presented and the species differences between human and mouse CAR were demonstrated. In addition, the possible binding modes of the ligands were predicted with an induced-fit docking approach, which accommodates receptor flexibility local to the binding site during the docking procedure.