Protein yapısal verisinin protein-protein etkileşim ağlarıyla geniş çapta birleştirilmesi

Protein-protein interaction networks provide a global picture of cellular function and biological processes. Structural prediction and modeling of protein-protein interactions at the network level is crucial; it helps in assigning protein function, elucidating functional mechanisms, and drug discovery. In the first part of this dissertation, we illustrate the importance of integrating protein structural information into interaction networks, particularly in identification of selective drug targets or drugs targeting multiple proteins. Next, we present a large, proteome-scale strategy that predicts protein associations based on interface structural motifs, to analyze human ubiquitination pathway. Substrate ubiquitination is mediated by the interactions between E2 enzymes and E3 ligases. Although these E2 and E3 proteins function in a concerted manner, the principles of selectivity between them are still not entirely understood. Our method allows elucidation of which E3s interact with which E2s and how they interact with each other. Interface analysis of E2-E3 complexes reveals important clues for inferring the specificity of the interactions. In the last part, the focus is directed towards studying circadian clock regulation in p53-deficient background. p53-deficient cells are prone to tumorigenesis and cancer. However, upon circadian clock disruption by Cry knockout, they show an increased sensitivity to apoptosis by genotoxic agents and hence are protected from the early onset of cancer. We aim to elucidate how apoptotic signals are activated in p53-null cells upon Cry knockout by combining experiments with a large-scale computational approach. In particular, we perform a large-scale integration of microarray expression profiles with protein-protein interaction networks. As such, we observe that the expressions of several apoptotic genes are increased upon Cry knockout in p53-null cells and a minor amount of genes would promote cell survival leading to, in overall, a shift towards cell apoptosis. In addition, we highlight the pathways that intersect with circadian clock and illustrate how these pathways response to circadian clock disruption. Our findings would assist in identifying targets in treatment of cancers associated with p53-deficiency.