Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum

Ann L. White, Bernadette Guerra, Robert E. Lanford

    Research output: Contribution to journalArticlepeer-review

    56 Scopus citations

    Abstract

    Plasma levels of lipoprotein(a) (Lp(a)) vary over 1000-fold between individuals and are determined by the gene for its unique apolipoprotein, apo(a), which has greater than 100 alleles. Using primary baboon hepatocyte cultures, we previously demonstrated that differences in the ability of apo(a) allelic variants to escape the endoplasmic reticulum (ER) are a major determinant of Lp(a) production rate. To examine the reason for these differences, the folding of newly synthesized apo(a) was analyzed in pulse- chase experiments. Samples were harvested in the presence of N- ethylmaleimide to preserve disulfide-bonded folding intermediates, and apo(a) was analyzed by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. Apo(a) required a prolonged period (30-60 min) to reach its fully oxidized form. Multiple folding intermediates were resolved, including a disulfide-linked, apo(a)-containing complex. Unexpectedly, all allelic variants examined showed similar patterns and kinetics of folding. Even 'null' apo(a) proteins, which are unable to exit the ER, appeared to fold normally. The ER glucosidase inhibitor, castanospermine, prevented apo(a) secretion, but did not inhibit folding. This suggests that an event which is dependent on trimming of N-linked glucoses, and which occurs after the folding events detectable in our assay, is required for apo(a) secretion. Differences in the ability to undergo this event may explain the variable efficiency with which apo(a) allelic variants exit the ER.

    Original languageEnglish (US)
    Pages (from-to)5048-5055
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume272
    Issue number8
    DOIs
    StatePublished - Feb 21 1997

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Fingerprint Dive into the research topics of 'Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum'. Together they form a unique fingerprint.

    Cite this