Redox Regulation of Rac1 Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
Creator
  • Mitchell, Lauren Elizabeth
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • Rac1 is a ubiquitous 21 kD guanine nucleotide binding protein that is a member of a large superfamily of GTPases, which plays a central role in fundamental cell processes, including cell motility and morphology, gene expression, cell cycle control and survival, as well as cell redox homeostasis. Because Rac1 is involved in so many important processes, deregulated Rac1 activity can yield a number of pathological conditions, such as cancer, cardiovascular disease, and neurological disorders. Mounting evidence suggests that a number of small GTPases, including Rac1, can be regulated by redox agents, and the Campbell lab has demonstrated that a subset of small GTPases have a redox-active Cys proximal to their active site, which can interact with oxidants and alter activation. I demonstrated that the redox-active Cys in Rac1 has a lowered pKa and is likely to be oxidized at a physiological pH; I selectively oxidized this Cys residue in Rac1 and characterized this modified form of the protein. Further, given recent observations that Rac1 interacts with SOD1 in a redox- and nucleotide-dependent manner, I initiated biochemical and biophysical analyses to quantify and characterize this novel interaction. Replacing the redox active cysteine with an aspartate residue (sulfonated Cys mimetic) abrogated the interaction, which suggests that sulfonic acid oxidation of Rac1 may perturb binding interactions with SOD1. In addition, I identified certain regions in Rac1 that are perturbed upon interaction with SOD1 by NMR.
Date of publication
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Campbell, Sharon
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
Language
Publisher
Parents:

This work has no parents.

Items