title: Proteolytic processing of human preproapolipoprotein A-I. A proposed defect in the conversion of pro A-I to A-I in Tangier's disease.
abstract: The primary translation product of human intestinal apolipoprotein A-I mRNA was isolated from wheat germ and ascites cell-free translation systems. Comparison of its NH2-terminal sequence with that of plasma high density lipoprotein-associated A-I showed that it is initially synthesized as a preproprotein. Like rat preproapolipoprotein A-I, it contains an 18-amino acid prepeptide and a 6-amino acid propeptide. The highly unusual COOH-terminal Gln-Gln dipeptide present in the rat pro-segment is also represented at the same position in the human sequence. The functional division of the 24-amino acid NH2-terminal extention into pro- and presegments was verified by finding that the stable intracellular form of A-I in a human hepatoma cell line was the proprotein. Edman degradation of radiolabeled intracellular and extracellular A-I indicated that this apolipoprotein was secreted without proteolytic cleavage of its hexapeptide prosegment. Therefore, it appears that apolipoprotein A-I undergoes an additional proteolytic processing step before it is fully integrated into plasma high density lipoprotein. Two-dimensional gel electrophoresis of purified proapolipoprotein A-I isolated from the hepatocyte cell culture media indicated that it corresponds to isoforms 2 and 3, the basic A-I isoproteins which are the precursors of plasma A-I and the predominant plasma A-I isoforms found in patients with Tangier's disease (Zannis, V. I., Lees, A. M., Lees, R. S., and Breslow, J. L. (1982) J. Biol. Chem., 257, 4978-4986). Therefore this pathologic state probably arises from a defect in the conversion of proapolipoprotein A-I to apolipoprotein A-I.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007009:Hypolipoproteinemias / Q000235:genetics*; D007583:Jejunum / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D010944:Plants / Q000378:metabolism; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D013045:Species Specificity; D013631:Tangier Disease / Q000235:genetics*; D014908:Triticum / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D001054:Apolipoproteins A; D008075:Lipoproteins, HDL; D011498:Protein Precursors; D012333:RNA, Messenger; C035250:preproapolipoprotein A-I