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Journal of Lipid Research, Vol. 45, 366-377, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Amino acid sequences within the ß1 domain of human apolipoprotein B can mediate rapid intracellular degradation

Louis R. Lapierre^*, Deborah L. Currie^*, Zemin Yao, Jianjun Wang and Roger S. McLeod^1,*

^* Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4E9
Department of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901-4413

¹ To whom correspondence should be addressed. e-mail: rmcleod2{at}dal.ca

Apolipoprotein B (apoB)-48 contains a region termed the ß1 domain that is predicted to be composed of extensive amphipathic ß-strands. Analysis of truncated apoB variants revealed that sequences between the carboxyl termini of apoB-37 and apoB-42 governed the secretion efficiency and intracellular stability of apoB. Although apoB-37, apoB-34, and apoB-29 were stable and secreted efficiently, apoB-42 and apoB-100 were secreted poorly and were degraded by an acetyl-leucyl-leucyl-norleucinal (ALLN)-sensitive pathway. Amino acid sequence analysis suggested that a segment between the carboxyl termini of apoB-38 and apoB-42 was 63% homologous to fatty acid binding proteins (FABPs), which contain orthogonal ß-sheets. To test the hypothesis that sequences from the ß1 domain are involved in apoB degradation, fusion proteins were created that contained apoB-29 linked to fragments derived from the ß1 domain of apoB or to liver FABP. Fusion proteins containing the ß1 domain segments apoB-34–42 or apoB-37–42 were degraded rapidly, whereas other fusion proteins were stable and secreted efficiently. Degradation was ALLN-sensitive, and the apoB-34–42 segment increased the association of the apoB protein with the cytosolic surface of the microsomal membrane.

Our data suggest that the presence of specific sequences in the ß1 domain of human apoB increases degradation by promoting the cytosolic exposure of the protein, although not all regions of the ß1 domain are functionally equivalent.

Abbreviations: ALLN, acetyl-leucyl-leucyl-norleucinal; apoB, apolipoprotein B; ER, endoplasmic reticulum; FABP, fatty acid binding protein; MTP, microsomal triglyceride transfer protein; PDI, protein disulfide isomerase; PNS, post-nuclear supernatant; PVDF, polyvinylidene difluoride; TG, triglyceride

Supplementary key words endoplasmic reticulum-associated degradation • proteasome • translocation

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