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Human DPP III – Keap1 Interactions : A Combined Experimental And Computational study

Gundić, Mario; Tomić, Antonija; Wade, Rebecca C.; Matovina, Mihaela; Karačić, Zrinka; Kazazić, Saša; Tomić, Sanja (2016) Human DPP III – Keap1 Interactions : A Combined Experimental And Computational study. Croatica Chemica Acta, 89 (2). pp. 217-228. ISSN 0011-1643

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Abstract

Kelch-like ECH associated protein 1 (Keap1) is a cellular sensor for oxidative stress and a negative regulator of the transcription factor Nrf2. Keap1 and Nrf2 control expression of nearly 500 genes with diverse cytoprotective functions and the Nrf2-Keap1 signaling pathway is a major regulator of cytoprotective responses to oxidative and electrophilic stress. It was found that the metallopeptidase dipeptidyl peptidase III (DPP III) contributes to Nrf2 activation by binding to Keap1, probably by binding to the Kelch domain, and thereby influences Nrf2 activity in cancer. We here first determined that the KD of the DPP III-Kelch domain complex is in the submicromolar range. In order to elucidate the molecular details of the DPP III – Kelch interaction we then built models of the complex between human DPP III and the Keap1 Kelch domain and performed coarse-grained and atomistic simulations of the complexes. In the most stable complexes, the ETGE motif in the DPP III flexible loop binds near the central pore of the six-blade β-propeller Kelch domain. According to the preliminary HD exchange experiments DPP III binds to the more unstructured end of Kelch domain. According to the results of MD simulations DPP III binding to the Kelch domain does not influence the overall DPP III structure or the long-range domain fluctuations. We can conclude that DPP III forms the stable complexes with the Keap1 Kelch domain by inserting the flexible loop into the entrance to the central pore of the six blade β- propeller Kelch domain at its more unstructured, N-terminus.

Item Type: Article
Additional Information: This work was supported by the Croatian Science Foundation (Project: "7235 Flexibility, activity and structure correlations in the dipeptidyl peptidase III family", the Croatian National Grid Infrastructure (CRO NGI, http://www.cro-ngi.hr/), the Alexander von Humboldt Foundation (Project:, Study of plant enzymes from metallopeptidase families M20 and M49"), the Klaus Tschira Foundation, and by European Union's Seventh Framework Programme for Research and Technological Development under grant agreement No. 316289 InnoMol, FP7-REGPOT-2012-2013-1
Uncontrolled Keywords: 'protein-protein interaction' ; dipeptidyl peptidase III ; docking ; molecular dynamics ; Keap1 ; microscale thermophoresis (MST)
Subjects: NATURAL SCIENCES > Chemistry
NATURAL SCIENCES > Chemistry > Physical Chemistry
NATURAL SCIENCES > Chemistry > Theoretical Chemistry
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions: Division of Organic Chemistry and Biochemistry
Projects:
Project titleProject leaderProject codeProject type
Povezanost fleksibilnosti, aktivnosti i strukture u porodici dipeptidil-peptidaza III-FlAcSSanja TomićIP-2013-11-7235HRZZ
Enhancement of the Innovation Potential in SEE through new Molecular Solutions in Research and Development-INNOMOLUNSPECIFIED316289EK
Depositing User: Mihaela Matovina
Date Deposited: 29 Apr 2020 12:27
Last Modified: 29 Apr 2020 12:27
URI: http://fulir.irb.hr/id/eprint/5460
DOI: 10.5562/cca2916

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