@phdthesis{oai:oist.repo.nii.ac.jp:00002934,
 author = {Pascarelli, Stefano},
 month = {2023-05-19, 2023-05-19},
 note = {Proteins participate in every important aspect of known living. The amino acid sequence of which a protein is composed contains information about the physicochemical properties, the three-dimensional structure, and its function. However, connecting protein sequence to function is still an open challenge, particularly for protein families with complex inter-relationships, i.e., heteromeric interactions. Such is the case of the Epidermal Growth Factor (EGF) receptor system, comprising four or more paralogs of the EGF receptor interacting with seven or more paralogs of the peptide ligand.
In this thesis, I use the evolutionary history of the EGF receptor system to show how phylogenetic patterns of evolution relate to functional divergence at the protein sequence level. By combining measures of residue conservation and residue co-evolution I developed a method to identify residues responsible of a specific protein function. Mutations on the residues highlighted by this method altered the auto-phosphorylation level of the EGF receptor and affected cellular growth. Next, I studied a fish-specific gene duplication of the EGF receptor and used it to describe and model a rare pattern of sequence evolution. I showed that this pattern could be related to functional divergence, thus providing a way to identify the occurrence of the event and the residues responsible of it. Ultimately, I analyzed whole protein families using protein similarity networks. My results showed how the networks made from structural similarity of predicted 3D-models give a better representation of the protein functions compared to sequence similarity networks, thus supporting a paradigm shift from sequence-based to predicted-structure-based bioinformatics software.
Overall, my thesis shows a deep interconnection between functional divergence and protein sequence evolution that can be exploited for prediction of function or identification of evolutionary events. The conceptual foundations of this study could be used in other fields where gene duplication and functional residues play an important part, as for example protein engineering and the study of copy number variation in cancer biology.},
 school = {Okinawa Institute of Science and Technology Graduate University},
 title = {タンパク質の配列、構造、ダイナミクスが解き明かすタンパク質機能の多様性},
 year = {}
}