Protein-protein interactions and the characterization of adipocyte fatty acid binding protein.

Thompson, Brian Raymond
2009-01

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Protein-protein interactions and the characterization of adipocyte fatty acid binding protein.

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2009-01

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Adipose tissue functions to not only store and provide an energy source in the form of triacylglycerol but to signal the nutritional status of those reserves through the secretion of adipokines and lipids. In obesity, this homeostatic regulation of whole body lipid metabolism is compromised resulting in disease states, such as type 2 diabetes and atherosclerosis. Adipocyte fatty acid binding protein, AFABP/aP2, functions to solubilize and traffic fatty acids, and other lipid metabolites, within the aqueous environment of the adipocyte. AFABP/aP2 knockout mice are resistance to diet and genetic induced obesity linked insulin resistance, while still being obese. The molecular mechanisms of this uncoupling of obesity and insulin resistance have not been elucidated. The identification and characterization of HSL and JAK2 as interacting partners of AFABP/aP2 are presented here. Fatty acid binding by AFABP/aP2 is necessary for the interactions, as indicated by the loss of interactions with the fatty acid binding mutant R126L/Y128F of AFABP/aP2. The phosphorylation state of HSL and JAK2 regulates their interaction with AFABP/aP2. An ExYK motif in AFABP/aP2, DDYMK, in the helix-turn-helix domain is the site of these interactions and a similar ExYK motif in HSL and JAK2 are important for these interactions. We propose that AFABP/aP2 is a fatty acid sensor, through lipid-regulated interaction, from AFABP/aP2's helix-turn-helix domain to an ExYK motif in HSL and JAK2. Furthermore, through its lipid-regulated interactions, AFABP/aP2 is a homeostatic regulator of whole body lipid metabolism, coordinating gene expression, signal transduction and metabolism.

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University of Minnesota Ph.D. dissertation. January 2009. Major: Biochemistry, Molecular Biology, and Biophysics. Advisor: David A. Bernlohr. 1 computer file (PDF); vi, 139 pages. Ill. (some col.)

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