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J. Biol. Chem., Vol. 278, Issue 45, 44702-44707, November 7, 2003

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Identification of the Lipoprotein Initiating Domain of Apolipoprotein B^*

Gregory S. Shelness, Li Hou, Aubrey S. Ledford, John S. Parks, and Richard B. Weinberg¶

From the Departments of Pathology and ^¶Internal Medicine and Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040

We have explored the minimum sequence requirement for the initiation of apolipoprotein B (apoB)-mediated triglyceride-rich lipoprotein assembly. A series of apoB COOH-terminal truncation mutants, spanning a range from apoB34 (amino acid residues 1–1544 of apoB100) to apoB19 (residues 1–862) were transfected into COS cells with and without coexpression of the microsomal triglyceride transfer protein (MTP). ApoB34, -25, -23, -21, -20.5, and -20.1 underwent efficient conversion to buoyant lipoproteins when coexpressed with MTP. ApoB19.5 (amino acids 1–884) also directed MTP-dependent particle assembly, although at reduced efficiency. When apoB19.5 was truncated by another 22 amino acids to form apoB19, MTP-dependent lipoprotein assembly was abolished. Analysis of the lipid stoichiometry of secreted lipoproteins revealed that all apoB truncation mutants formed spherical particles containing a hydrophobic core. Even highly truncated assembly-competent forms of apoB, such as apoB19.5 and 20.1, formed lipoproteins with surface:core lipid ratios of <1. We conclude that the translation of the first 884 amino acids of apoB completes a domain capable of initiating nascent lipoprotein assembly. The composition of lipids recruited into lipoproteins by this initiating domain is consistent with formation of small emulsion particles, perhaps by simultaneous desorption of both polar and neutral lipids from a saturated bilayer.

Received for publication, July 14, 2003 , and in revised form, August 25, 2003.

^* This work was supported by National Institutes of Health Grants HL49373 (to G. S. S. and J. S. P.), HL54176 (to J. S. P), and HL30897 (to R. B. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 336-716-3282; Fax: 336-716-6279; E-mail: gshelnes{at}wfubmc.edu.

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