Hydrolysis of triacylglycerols by lipoprotein lipase (LPL) is essential for normal lipid metabolism. LPL does not fold and function properly without a newly identified, transmembrane protein, lipase maturation factor (LMF1). LMF1 is essentially uncharacterized;in fact it belongs to a family of proteins with a similar """"""""domain of unknown function"""""""" (Duf1222). The major goal of this project is to investigate the interaction between LPL and LMF1. By analogy to lipases with structural characteristics similar to LPL, we propose that LMF1 acts as a """"""""private foldase"""""""" for LPL.
In Aim 1, I will use biochemical assays and assays in cells to determine why LPL needs folding assistance and how LMF1 helps LPL fold.
Aim 2 consists of analysis of the membrane topology and structure of LMF1. Finally, Aim 3 focuses on the observation that many human pathogens have Duf1222 proteins;therefore I will use computational and biochemical approaches to determine if the Duf1222 protein represents one-half of a foldase-lipase pair. During the mentored phase, I will build on my preliminary observations to develop a model for LMF1 membrane topology. Additionally I will begin biochemical and structural analyses of the LMF-LPL interaction, and begin preliminary work on aim 3. For the independent phase, I will continue structural analysis of LMF1 and expand my biochemical analysis to Duf1222 proteins in other species to determine if they have important roles in lipid metabolism.
Cardiovascular disease is a leading cause of death in the developed world, and elevated blood triacylglycerol is a risk factor. LPL deficiency results in elevated blood triacylglycerol and disturbs overall lipid metabolism. LMF1 promotes LPL activity through a poorly understood process, and elucidation of this mechanism will provide a foundation to begin to ameliorate one cause of LPL deficiency.
|Roberts, Benjamin S; Babilonia-Rosa, Melissa A; Broadwell, Lindsey J et al. (2018) Lipase maturation factor 1 affects redox homeostasis in the endoplasmic reticulum. EMBO J 37:|
|Babilonia-Rosa, Melissa A; Neher, Saskia B (2014) Purification, cellular levels, and functional domains of lipase maturation factor 1. Biochem Biophys Res Commun 450:423-8|