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New findings about human dipeptidyl peptidase III based on mutations found in cancer

Matovina, Mihaela; Agić, Dejan; Abramić, Marija; Matić, Sara; Karačić, Zrinka; Tomić, Sanja (2017) New findings about human dipeptidyl peptidase III based on mutations found in cancer. RSC Advances, 7 (58). pp. 36326-36334. ISSN 2046-2069

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Dipeptidyl peptidase III (DPP III) is a cytosolic enzyme belonging to the metallopeptidase family M49, involved in the final steps of protein catabolism. More than a hundred missense mutations can be found in the coding region of the human DPP3 gene when searching cBioPortal for Cancer Genomics. The role of two highly conserved residues in the family M49, whose mutations G313W and R510W were detected in human cancer, was investigated using combined experimental and computational approaches (substrate docking and MD simulations). Several mutants of human DPP III were expressed and purified as recombinant proteins, and their biochemical properties were determined. The conservative substitution of Arg510 with lysine mildly decreased enzyme activity activity for Arg-Arg-2-naphtylamide substrate, while the substitutions of Arg510 with glutamine and Gly313 with alanine substantially decreased enzyme activity, and tryptophan substitutions found in cancer, G313W and R510W, almost abolished enzyme activity. MD simulations showed that substitution of Gly313, and especially Arg510 with tryptophan, significantly increases the enzyme flexibility, particularly that of the binding site including the H450ELLGH455 motif, and influences the substrate interactions with the catalytic His568. The results clearly indicate that, besides the enzyme structure, its dynamics properties also significantly influence the human DPP III activity.

Item Type: Article
Uncontrolled Keywords: dipeptidyl peptidase III ; mutations in cancer ; MD simulations
Subjects: NATURAL SCIENCES > Physics
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Povezanost fleksibilnosti, aktivnosti i strukture u porodici dipeptidil-peptidaza III-FlAcSSanja TomićIP-2013-11-7235HRZZ
Depositing User: Mihaela Matovina
Date Deposited: 16 Jul 2019 11:39
DOI: 10.1039/C7RA02642K

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