Grant: $276,481 - National Institutes of Health - Sep. 30, 2009
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Award Description: Continual dynamic remodeling of the actin cytoskeleton, in response to intrinsic and extrinsic signals, is critical for the execution of many eukaryotic cell functions including cell cycle progression, cell motility, secretion and recovery from cellular/environmental stress. These dynamic rearrangements are regulated by a large, and as yet incompletely defined or understood, battery of actin binding proteins. This proposal seeks to continue investigations on the functions of three novel regulators of actin dynamics: the NADPH oxidoreductase Old Yellow Enzyme (Oye2p; Aim #1), the MAPKKK Ssk2p (Aim #2), and the cofilin activator Aip1p (Aim #3). Our previous work on Oye2p suggests that it controls the redox state of a C285-C374 disulfide bond in actin that can in turn affect F-actin stability, sensitivity to oxidative stress and cell death/aging. We propose to extend those studies to investigate how actin oxidation alters actin dynamics and how the cell regulates the organization of its F-actin structures during the response to, and recovery from, oxidative stress. In particular we seek to identify the components of F-actin containing oxidized actrin bodies that form upon a severe oxidative stress. The Ssk2p kinase facilitates re-polarization of the actin cytoskeleton following osmotic stress. Our studies on this conserved protein, and the adaptation to osmotic stress, will be extended by identifying the relevant substrates of the kinase that drive re-polarization of the actin cytoskeleton employing a candidate protein approach and by identifying associated proteins by mass-spectrometry. Aip1p is a conserved cofactor of the small actin binding protein cofilin. These two proteins act in concert to destabilize actin filaments in vitro and drive actin dynamics in vivo in diverse actin networks. Structure/function analysis of the Aip1p-cofilin complex has led to a model for the complex; we seek to continue these studies in order to further refine this model to gain further insight into the mechanism of F-actin de-stabilization by cofilin. This approach will take advantage of our recently identified gain of function mutants in cofilin for which we have sub-two angstrom crystallography data.
Project Description: As defined in the Award Description field
Infrastructure Description: Not applicable
Jobs Summary: Not applicable for this reporting period (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 30, 2009. Help expand these official descriptions using the wiki below.