| Summary: | Apolipoprotein B (apoB)-48 contains a region termed the β1 domain that is predicted to be composed of extensive amphipathic β-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 β-sheets. To test the hypothesis that sequences from the β1 domain are involved in apoB degradation, fusion proteins were created that contained apoB-29 linked to fragments derived from the β1 domain of apoB or to liver FABP. Fusion proteins containing the β1 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 β1 domain of human apoB increases degradation by promoting the cytosolic exposure of the protein, although not all regions of the β1 domain are functionally equivalent.
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