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Investigating the roles of p53 stability and its interactions with chaperone proteins during mitochondrial permeability transition

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dc.contributor.advisor Seeliger, Markus A en_US
dc.contributor.advisor Moll, Ute en_US
dc.contributor.author Lebedev, Ivan en_US
dc.contributor.other Department of Biochemistry and Structural Biology en_US
dc.date.accessioned 2017-09-20T16:51:29Z
dc.date.available 2017-09-20T16:51:29Z
dc.date.issued 2016-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76942 en_US
dc.description 154 pgs en_US
dc.description.abstract Tissue necrosis as a consequence of ischemia-reperfusion injury and oxidative damage is a leading cause of permanent disability and death worldwide. The complete mechanism by which cells undergo necrosis upon oxidative stress is not understood. In response to an oxidative insult, wildtype p53 has been implicated as a central regulatory component of the mitochondrial permeability transition (mPT), triggering necrosis. This process is associated with cellular stabilization and translocation of p53 into the mitochondrial matrix. I explore the mechanism by which p53 activates the key mPT regulator cyclophilin D (CypD); how the stability of p53 affects its ability to interact with CypD; and how Trap1, an Hsp90-related mitochondrial matrix chaperone protein and member of the mitochondrial unfolded protein response (mtUPR), is able to suppress mPT in a p53-dependent manner. I find that p53 needs to be structurally destabilized in order to interact with CypD and that catalytically active CypD causes strong aggregation of wildtype p53 protein (both full length and isolated DNA binding domain) into amyloid-type fibrils in vitro. NMR studies of CypD reveal slow exchange behavior, characteristic of a dynamic process such as isomerization. Moreover, I find that inhibition of Trap1 by the mitochondria-specific HSP90 ATPase antagonist gamitrinib strongly sensitizes primary mouse embryonic fibroblasts (MEFs) to mPT and permeability transition pore (mPTP) opening in a p53- and CypD-dependent manner. The result of my work proposes a model by which influx of unfolded p53 into the mitochondrial matrix in response to oxidative stress indirectly activates the normally inhibited CypD by displacing it from Trap1 complexes. This activates CypD's isomerase activity. Liberated CypD then isomerizes multiple proteins including p53 (causing p53 aggregation) and the structural components of the mPTP pore, inducing pore opening. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biology en_US
dc.subject.other CypD, mPTP, Necrosis, p53, Stroke en_US
dc.title Investigating the roles of p53 stability and its interactions with chaperone proteins during mitochondrial permeability transition en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Glynn, Steven E en_US
dc.contributor.committeemember Bowen, Mark E en_US
dc.contributor.committeemember Bogenhagen, Daniel en_US


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