Flexibility, activity and structure correlations in the dipeptidyl peptidase III family, (FlAcS, ID:7235)
Sanja Tomić, dr.sc.
+385 1 457 1251
Within the project frame we intend to investigate diversity in evolutionary conserved metallopeptidase family M49 (DPP III family) through characterization of catalytic, structural and dynamical properties of its members. The project would encompass five dipeptidyl peptidases III (DPP III): human, yeast, two bacterial orthologs, from thermophileCaldithrix abyssiand oral pathogenPorphyromonas gingivalis, and a DPP III from plantPhyscomitrella patens. The DPP III cleaves dipeptides from the N-terminus of many oligopeptides and contributes to the intracellular protein metabolism as well as to endogenous defense against oxidative stress. Human DPP III (h.DPP III) is also related to pathological processes of cataractogenesis, tumor growth and influenza virus infection. The project research should elucidate whether the large flexibility determined for h.DPP III is conserved within DPP IIIs, and how it correlates with the protein function. It would reveal submolecular details important for substrate stabilization and, in the case of h.DPP III, the enzymatic mechanism. Elucidation of the key interactions between h.DPP III and Keap1 protein (Nrf2-Keap1 signalling pathway is major regulator of cytoprotective responses to oxidative and electrophilic stress), and possible correlation of DPP III flexibility with the complex stability, should aid in clarification of its cellular roles. Plant DPP III, differently from DPP IIIs in other organisms possesses a NUDIX box. The project should elucidate its potential dual activity (peptidase and NUDIX). Study of DPP III from thermophile should improve our knowledge on thermophile proteins, potentially useful in biotechnology. In order to fulfill the outlined goals a finely tuned multidisciplinary approach would be used in which molecular biology, biochemistry and mass spectrometry methods would be complemented with bioinformatics, multiscale molecular modelling (coarse-grained/all-atom MD, QM/MM) and macromolecular crystallography