Uloga dipeptidil-peptidaze III u oksidacijskom stresu

doctoral thesis

• Title (english): Role of dipeptidyl peptidase III in oxidative stress response
• Author: Sara Matić
• Mentor: Sanja Tomić (mentor)
• Mentor: Mihaela Matovina (komentor)
• Committee member: Branimir Bertoša (predsjednik povjerenstva)
• Committee member: Jasmina Rokov Plavec (član povjerenstva)
• Committee member: Filip Šupljika (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2021-09-30, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Razvoj bolesti često je posljedica deregulacije staničnih signalnih putova. Proučavanje
interakcija protein-protein kombinacijom eksperimentalnih i računalnih pristupa omogućuje
razumijevanje tih staničnih procesa na molekulskoj razini. Signalni put KEAP1 – NRF2,
ključan za citoprotektivni odgovor i preživljavanje stanica, često je dereguliran u stanicama
raka. KEAP1 je stanični senzor oksidacijskog stresa i represor transkripcijskog faktora NRF2.
U uvjetima oksidacijskog stresa dipeptidil-peptidaza III (DPP III) se može kompetitivno vezati
na KEAP1 i inducirati oslobađanje NRF2, što potiče antioksidacijski odgovor putem
transkripcije citoprotektivnih gena. Korištenjem simulacija molekulske dinamike te izotermne
titracijske kalorimetrije i termoforeze proučavan je mehanizam vezanja KEAP1 – DPP III, kako
za divlji tip proteina, tako i za mutirane varijante pronađene u stanicama raka. Razumijevanje
strukturnih i energetskih učinaka mutacija na brzinu i afinitet vezanja KEAP1 i DPP III u
konačnici pojašnjava na koji način navedene mutacije mogu modificirati odgovor stanica raka
na kemoterapiju i preživljavanje oksidacijskog stresa.

Abstract (english)

Disease development is often due to deregulation of cellular signaling pathways. Proteinprotein interactions study using a combination of experimental and computational approaches
allows understanding of these cellular processes at the molecular level. The KEAP1 – NRF2
signaling pathway, crucial for cytoprotective response and cell survival, is often deregulated in
cancer cells. KEAP1 is a cellular oxidative stress sensor and a repressor of NRF2 transcription
factor. Under oxidative stress, dipeptidyl peptidase III (DPP III) can competitively bind to
KEAP1, inducing NRF2 release and antioxidative response via transcription of cytoprotective
genes. Using molecular dynamics simulations, isothermal titration calorimetry and microscale
thermophoresis, the mechanism of KEAP1 – DPP III binding was studied for wild-type and
mutant variants found in cancer cells. Knowledge of the structural and energetic effects that
mutations have on the binding rate and the affinity of KEAP1 - DPP III complexation, enables
better understanding of their influence on the cancer cell response to chemotherapy.

• Keywords: DPP III; KEAP1; proteinske interakcije; simulacije molekulske dinamike; mutacije u rak
• Keywords (english): DPP III; KEAP1; protein interactions; molecular dynamics simulatoins; cancer mutations
• Language: croatian
• URN:NBN: urn:nbn:hr:217:768164
• Promotion: 2021
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 115 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2022-03-30
• Created on: 2021-10-22 13:18:25