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J Biol Chem, Vol. 274, Issue 4, 1986-1993, January 22, 1999

Identification of Domains in Apolipoprotein B100 That Confer a High Requirement for the Microsomal Triglyceride Transfer Protein

Edwige Nicodeme, Fabienne Benoist, Roger McLeod^¶, Zemin Yao^¶, James Scott, Carol C. Shoulders, and Thierry Grand-Perret

From the  Laboratoire GlaxoWellcome, Centre de Recherche, 25 avenue du Quebec, ZA de Courtaboeuf, 91951 Les Ulis cedex, France, the ^¶ Lipoprotein and Atherosclerosis Group, University of Ottawa Heart Institute, Ottawa Civic Hospital, Ottawa, Ontario K1Y 4E9, Canada, and the  Medical Research Council Molecular Medicine Group, Medical Research Council Clinical Sciences Center, Imperial College School of Medicine, Du Cane Road, London W12 0NN, United Kingdom

The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apoB-containing lipoproteins. To investigate the role of MTP in lipoprotein assembly, we determined the ability of carboxyl-terminally truncated forms of apoB to be secreted from cells treated with the MTP inhibitor 4'-bromo-3'-methylmetaqualone (Benoist, F., Nicodeme, E., and Grand-Perret, T. (1996) Eur. J. Biochem. 240, 713-720). In Caco-2 and mhAT3F cells that produce apoB100 and apoB48, the inhibitor preferentially blocked apoB100 secretion. When the inhibitor was tested on McA-RH7777 cells stably transfected with cDNAs encoding human apoB100, apoB72, apoB53, apoB29, and apoB18, the secretion of apoB100, apoB72, and apoB53 was preferentially impaired relative to apoB48 and shorter forms. To delineate the region between apoB48 and apoB53 that has a high requirement for MTP, we used puromycin to generate a range of truncated forms of apoB in HepG2 cells. The secretion of apoB53 and longer forms of apoB was markedly affected by low concentrations of the MTP inhibitor (~ 1 µM), whereas apoB51 and smaller forms of apoB were only affected at higher concentrations (> 10 µM). The size-related sensitivity to MTP inhibitor was not due to late processing or retention, since the same result was observed when nascent lipoproteins were isolated from the endoplasmic reticulum. The MTP inhibitor did not alter the density of the secreted lipoproteins, indicating that each apoB polypeptide requires a minimally defined amount of lipid to attain a secretable conformation. Our results suggest that the folding of the domain between apoB51 and apoB53 has a high requirement for lipid. This domain is predicted to form amphipathic -helices and to bind lipid reversibly. It proceeds and is followed by rigid amphipathic -sheets that are predicted to associate with lipid irreversibly. We speculate that these domains enable apoB to switch from a stable lipid-poor conformation in apoB48 to another lipid-rich conformation in apoB100 during lipoprotein assembly.

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