Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Biochemistry

Supervisor(s)

Dr. David Litchfield

Abstract

Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that has been shown to be neuroprotective in aging-related neurodegenerative diseases such as Alzheimer's disease (AD). However, it is not active in AD brain, and a recent proteomic screen of Mild Cognitive Impairment (MCI) brain samples revealed that Pin1 is oxidized in the brains of these pre-AD patients. This suggests that this oxidation may be the cause of the loss of the neuroprotective Pin1 function in AD. The Pin1 active site contains a functionally critical cysteine residue (Cys113) with a low predicted pKa, making it highly susceptible to oxidation. We hypothesize that Pin1 is inhibited by oxidation of this cysteine. This hypothesis was tested using enzyme activity assays, mutational analysis, and structural studies. We conclude that the loss of Pin1 activity due to oxidation can be isolated to the oxidative modification of Cys113, and reveals a potential mechanism for countering this loss of function.


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