Using computational and experimental approaches to understand protein function : application to proprotein convertases and other disease-related proteins

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Elferich, Johannes
Oregon Health & Science University
Biophysics; Computational Biology; Endopeptidases; Proprotein Convertases; Secretroy Pathway; Histidine; Biochemistry, Biophysics, and Structural Biology
thesis / dissertation description
This thesis describes the combination of biochemical, biophysical, and computational tools to investigate the mechanism of pH-mediated activation of proprotein convertases. Proprotein convertases are a family of human serine endoproteases that are involved in processing of hormones, enzymes, and receptors. In order to spatiotemporally control this processing in distinct organelles of the secretory pathway proprotein convertases have evolved to sense the pH of the correct organelle to mediate activation. In this thesis I demonstrate (i) an enrichment of histidine residues in the propeptides of eukaryotic, but not prokaryotic, homologs of proprotein convertases and in propeptides of another eukaryotic pH activated protease family, (ii) that the propeptides of proprotein convertases sense pH and partially unfold at the pH of activation, (iii) and that proprotein convertases fine-tune the pH of their activation by using multiple titratable sites and adjusting the pKa values of a conserved histidine. Furthermore, this thesis describes other examples where the combination of computational biology with experimental methods allows a deeper understanding of the biology of proteins relevant in multiple diseases, ranging from protozoan parasites to cancer.