This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.One of the key players in the mechanisms that regulate the assembly of triacylglycerol (TAG)-rich lipoproteins (such as very low density lipoproteins, VLDL) and theirsecretion from the liver into the plasma is apolipoprotein (apo) B. ApoB is a very large (4536 amino acids and molecular mass of about 550 kDa), hydrophobic glycoprotein that directs the assembly of VLDL. VLDL particles are remodeled in the plasma to give rise to low density lipoproteins (LDL), the major carriers of plasma cholesterol, and represent a major risk factor for the premature development of coronary heart disease. The goal of this project is to elucidate the molecular details of the folding of apoB into its mature, secretion-competent form. This might allow the development of means to modulate the secretion of VLDL and, thereby, reduce plasma cholesterol levels. ApoB has unusual structural properties, as it is virtually water insoluble, and as a result has unusual folding requirements. Folding of nascent proteins in the cell is a complex process that requires the assistance of molecular chaperones, which are highly conserved proteins found in all types of cells from every species. The primary role of molecular chaperones is to bind transiently to nascent polypeptides, prevent their aggregation, and maintain them in conformations competent for efficient folding. Lipids and proteins precipitated with antibodies against apoB were characterized in comparison to LDL and HDL (high density lipoprotein), and in further collaboration with F.K. Welty (Harvard Medical School), lipids from normal LDL are compared to those associated with the mutant apolipoprotein B67. A new LC-MS based methodology was developed for the characterization of these lipids and applied together with classic nanospray MS (published as U.Sommer et al. (2006) in the Journal of Lipid Research. further analysis of boh proteins and lipids in these complexes is ongoing.
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