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Klinische Wochenschrift

, Volume 67, Issue 4, pp 225–237 | Cite as

The apolipoprotein multigene family: Structure, expression, evolution, and molecular genetics

Preisvorlesung

Summary

The plasma apolipoproteins can be classified into two subgroups: the soluble apolipoproteins including apolipoprotein (apo) A-I, A-II, A-IV, C-I, C-II, C-III, and E, and the apoBs including apoB-100 and apoB-48. The soluble apolipoproteins have very similar genomic structures, each having a total of three introns at the same locations; apoA-IV is an exception in that it has lost its first intron. Using the exon/intron junctions as reference points, we can obtain an alignment of the coding regions of all the soluble apolipoprotein genes. The mature peptide regions of the genes are almost completely made up of tandem repeats of 11 codons. The part of mature peptide region encoded by exon 3 contains a common block of 33 codons, whereas the part encoded by exon 4 contains a much more variable number of internal repeats of 11 codons. On the basis of the degree of homology of the various sequences, and the pattern of the internal repeats in these genes, an evolutionary tree has been proposed for the soluble apolipoprotein genes. ApoB-100 differs considerably from the soluble apolipoproteins. It is the largest apolipoprotein containing 4536 amino acid residues. Two types of internal repeats are identified in apoB-100: amphipathic α-helical repeats and proline-containing repeats with high β-sheet content. The apoB gene contains 29 exons and 28 introns. Its evolutionary relationship to the soluble apolipoprotein genes is unclear. The 3′ end of the apoB gene contains a region of variable number of tandem 12–16-base pair repeats. We have applied the polymerase chain reaction technique to characterize this highly polymorphic locus. The same technique can be used to accurately type other variable number of tandem repeats loci. Finally, apoB-48 was shown to be the product of an RNA editing mechanism involving an intestinal mRNA that has an in-frame UAA stop codon resulting from a C→U change in the codon CAA encoding Gln-2153 in apoB-100 mRNA. Using a molecular approach to apolipoprotein synthesis, structure and genetic analysis, we have generated information important to our understanding of lipoprotein metabolism; we also uncovered unexpected experimental results that are relevant to general cell and molecular biology and molecular evolution.

Key words

Atherosclerosis Apolipoprotein Gene expression Genetics Evolution Gene duplication Lipid binding DNA polymorphism Hypercholesterolemia 

Abbreviations

LDL

low density lipoproteins

HDL

high density lipoproteins

IDL

intermediate density lipoproteins

apo

apolipoprotein(s)

mRNA

messenger ribonucleic acid

VNTR

variable number of tandem repeats

PCR

polymerase chain reaction

Myr

million years

RFLP

restriction fragment length polymorphism(s)

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References

  1. 1.
    Goldstein JL, Brown MS (1977) The low density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 46:897–930Google Scholar
  2. 2.
    Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47Google Scholar
  3. 3.
    Innerarity TL, Mahley RW (1978) Enhanced binding by cultured human fibroblasts of apoE-containing lipoproteins as compared with low density lipoproteins. Biochemistry 17:1440–1447Google Scholar
  4. 4.
    Sherrill BC, Innerarity TL, Mahley RW (1980) Rapid hepatic clearance of the canine lipoproteins containing only the E apoprotein by high affinity receptor. J Biol Chem 255:1804–1807Google Scholar
  5. 5.
    Hui DY, Innerarity TL, Mahley RW (1981) Lipoprotein binding to canine hepatic membranes: metabolically distinct apoE and apoB,E receptors. J Biol Chem 256:5646–5655Google Scholar
  6. 6.
    LaRosa JC, Levy RI, Herbert P, Lux SZ, Frederickson DS (1970) A specific apoprotein activator for lipoprotein lipase. Biochem Biophys Res Commun 41:57–62Google Scholar
  7. 7.
    Breckenridge WC, Little JA, Steiner G, Chow A, Poapst M (1978) Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. N Eng J Med 298:1265–1273Google Scholar
  8. 8.
    Brown WV, Baginsky ML (1972) Inhibition of lipoprotein lipase by an apolipoprotein of human very low density lipoprotein. Biochem Biophys Res Commun 46:375–382Google Scholar
  9. 9.
    Wang CS, McConathy WJ, Kloer HU, Alaupovic P (1985) Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. J Clin Invest 75:384–390Google Scholar
  10. 10.
    Fielding CJ, Shore VG, Fielding PE (1972) A protein cofactor of lecithin-cholesterol acyltransferase. Biochem Biophys Rec Commun 46:1493–1498Google Scholar
  11. 11.
    Soutar AK, Garner CW, Baker HN, Sparrow JT, Jackson RL, Gotto AM Jr, Smith LC (1975) Effect of the human apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin-cholesterol acyltransferase. Biochemistry 14:3057–3064Google Scholar
  12. 12.
    Steinmetz A, Utermann G (1985) Activation of lecithin cholesterol acyltransferase by human apolipoprotein A-IV. J Biol Chem 260:2258–2264Google Scholar
  13. 13.
    Glomset JA (1968) The plasma lecithin-cholesterol acyltransferase reaction. J Lipid Res 9:155–167Google Scholar
  14. 14.
    Chan L, Jackson RL, O'Malley BW, Means AR (1976) Synthesis of very low density lipoproteins in the cockerel: effects of estrogen. J Clin Invest 58:368–379Google Scholar
  15. 15.
    Chan L (1983) Hormonal control of apolipoprotein synthesis. Annu Rev Physiol 45:615–623Google Scholar
  16. 16.
    Li WH, Tanimura M, Luo CC, Datta S, Chan L (1988) The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J Lipid Res 29:245–271Google Scholar
  17. 17.
    Blackhart BD, Ludwig EM, Pierotti VR, Caiati L, Onasch MA, Wallis SC, Pownell L, Pease R, Knott TJ, Chu ML, Mahley RW, Scott J, McCarthy BJ, Levy-Wilson B (1986) Structure of the human apolipoprotein B gene. J Biol Chem 261:15364–15367Google Scholar
  18. 18.
    Lux SE, Hirz R, Shrager RI, Gotto AM Jr (1972) The influence of lipid on the conformation of human plasma high density apolipoproteins. J Biol Chem 247:2598–2606Google Scholar
  19. 19.
    Jackson RL, Morrisett JD, Gotto AM Jr, Segrest JP (1975) The mechanism of lipid-binding by plasma lipoproteins. Molec Cellular Biochem 6:43–50Google Scholar
  20. 20.
    Jackson RL, Morrisett JD, Sparrow JT, Segrest JP, Pownall HJ, Smith LC, Hoff HF, Gotto AM Jr (1974) The interaction of apolipoprotein-serine with phosphatidylcholine. J Biol Chem 249:5314–5320Google Scholar
  21. 21.
    Segrest JP, Jackson RL, Morrisett JD, Gotto AM Jr (1974) A molecular theory of lipid-protein interactions in the plasma lipoproteins. FEBS Lett 38:247–258Google Scholar
  22. 22.
    Doolittle RF (1981) Similar amino acid sequences: chance or common ancestry? Science 214:149–159Google Scholar
  23. 23.
    Chen SH, Yang CY, Chen PF, Setzer D, Tanimura M, Li WH, Gotto AM Jr, Chan L (1986) The complete cDNA and amino acid sequence of human apolipoprotein B-100. J Biol Chem 261:12918–12921Google Scholar
  24. 24.
    Knott J, Pease RJ, Powell LM, Wallis SC, Rall SC Jr, Innerarity TL, Blackhart B, Taylor WH, Marcel YL, Milne R, Johnson D, Fuller M, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J (1986) Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323:734–738Google Scholar
  25. 25.
    Yang CY, Chen SH, Gianturco SH, Bradley WA, Sparrow JT, Tanimura M, Li WH, Sparrow DA, DeLoof H, Rosseneu M, Lee FS, Gu ZW, Gotto AM Jr, Chan L (1986) Sequence, structure, receptor binding domains and internal repeats of human apolipoprotein B-100. Nature 323:738–742Google Scholar
  26. 26.
    Law SW, Grant SM, Higuchi K, Hospattankar A, Lackner K, Lee N, Brewer HB (1986) Human liver apolipoprotein B-100 cDNA: complete nucleic acid and derived amino acid sequence. Proc Natl Acad Sci USA 83:8142–8146Google Scholar
  27. 27.
    Cladaras C, Hadzopoulou-Cladaras M, Nolte RT, Atkinson D, Zannis VI (1986) The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apoB-100 and apoB-48 forms. EMBO J 5:3495–3507Google Scholar
  28. 28.
    Gotto AM Jr, Levy RI, Frederickson DS (1968) Observations on the conformation of human beta-lipoprotein: evidence of the occurrence of beta structure. Proc Natl Acad Sci USA 60:1436–1441Google Scholar
  29. 29.
    Chen GC, Kane JP (1975) Temperature dependence of the optical activity of human serum low density lipoprotein. The role of lipids. Biochemistry 14:3357–3362Google Scholar
  30. 30.
    Osterman D, Mora R, Kezdy FJ, Kaiser ET, Meredit SC (1984) A synthetic amphiphilic beta-strand tridecapeptide: a model for apolipoprotein B. J Am Chem Soc 106:6845–6847Google Scholar
  31. 31.
    Barker WC, Dayhoff MO (1977) Evolution of lipoproteins deduced from protein sequence data. Comp Biochem Physiol 576:309–315Google Scholar
  32. 32.
    Fitch WM (1977) Phylogenetics constrained by the cross-over process as illustrated by human hemoglobins and a thirteen cycle, eleven amino acid repeat in human apolipoprotein A-I. Genetics 86:623–644Google Scholar
  33. 33.
    McLachlan AD (1977) Repeated helical pattern in apolipoprotein A-I. Nature 267:465–466Google Scholar
  34. 34.
    Karathanasis SK, Zannis VI, Breslow JL (1983) Isolation and characterization of the human apolipoprotein A-I gene. Proc Natl Acad Sci USA 80:6147–6151Google Scholar
  35. 35.
    Boguski MS, Freeman M, Elshourbagy NA, Taylor JM, Gordon JI (1986) On computer-assisted analysis of biological sequences: proline punctuation, consensus sequences, and apolipoprotein repeats. J Lipid Res 27:1011–1034Google Scholar
  36. 36.
    Luo CC, Li WH, Moore MN, Chan L (1986) Structure and evolution of the apolipoprotein multigene family. J Mol Biol 187:325–340Google Scholar
  37. 37.
    Fukushima D, Kupferberg JP, Yokoyama S, Kroon DJ, Kaiser ET, Kezdy FJ (1979) A synthetic amphipathic helical docasapeptide with the surface properties of plasma apolipoprotein A-I. J Am Chem Soc 101:3703–3704Google Scholar
  38. 38.
    Nakagawa SH, Lau HSH, Kezdy FJ, Kaiser ET (1985) The use of polymer-bound oximes for the synthesis of large peptides usable in segment condensation: synthesis of a 44 amino acid amphipathic peptide model of apolipoprotein A-I. J Am Chem Soc 107:7087–7092Google Scholar
  39. 39.
    Kaiser ET, Kezdy FJ (1983) Secondary structures of proteins and peptides in amphipathic environments (a review). Proc Natl Acad Sci USA 80:1137–1143Google Scholar
  40. 40.
    Kane JP, Hardman DA, Paulus HE (1980) Heterogeneity of apolipoprotein B: isolation of a new species from human chylomicron. Proc Natl Acad Sci USA 77:2465–2469Google Scholar
  41. 41.
    Kane JP (1983) Apoprotein B: structural and metabolic heterogeneity. Ann Rev Physiol 45:637–650Google Scholar
  42. 42.
    Yang CY, Gu ZW, Weng Sa, Kim TW, Chen SH, Pownall HJ, Sharp PM, Liu SW, Li WH, Gotto AM, Chan L (1989) Structure of apolipoprotein B-100 of human low density lipoproteins. Arteriosclerosis 9:96–108Google Scholar
  43. 43.
    Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J (1987) A novel form of tissue-specific RNA processing produces apolipoprotein B-48 in intestine. Cell 50:831–840Google Scholar
  44. 44.
    Chen SH, Habib G, Yang CY, Gu ZW, Lee BR, Weng Sa, Silberman SR, Cai SJ, Deslypere JP, Rosseneu M, Gotto AM Jr, Li WH, Chan L (1987) Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific inframe stop codon. Science 238:363–366Google Scholar
  45. 45.
    Knott TJ, Rall SC Jr, Innerarity TL, Jacobson SF, Urdea MS, Levy-Wilson B, Powell LM, Pease RJ, Eddy R, Nakai H, Byers M, Priestley LM, Robertson E, Rall LB, Betsholtz C, Shows TB, Mahley RW, Scott J (1985) Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science 230:37–43Google Scholar
  46. 46.
    Hirose N, Blankenship DT, Krivanek MA, Jackson RL, Cardian AD (1987) Isolation and characterization of four heparin-binding cyanogen bromide peptides of human plasma apolipoprotein B. Biochemistry 26:5505–5512Google Scholar
  47. 47.
    Cardin AD, Randall CJ, Hirose N, Jackson RL (1987) Physical-chemical interaction of heparin and human plasma low density lipoproteins. Biochemistry 26:5513–5518Google Scholar
  48. 48.
    Weisgraber KH, Rall SC Jr (1987) Human apolipoprotein B-100 heparin-binding sites. J Biol Chem 262:11097–11103Google Scholar
  49. 49.
    DeLoof H, Rosseneu M, Yang CY, Li WH, Gotto AM Jr, Chan L (1987) Human apolipoprotein B: analysis of internal repeats and homology with other apolipoproteins. J Lipid Res 28:1455–1465Google Scholar
  50. 50.
    Margolis S, Langdon RG (1966) Studies on human serum, beta1-lipoprotein. III. Enzymatic modifications. J Biol Chem 241:485–493Google Scholar
  51. 51.
    Chapman MJ, Goldstein S, Mills GL (1978) Limited tryptic digestion of human serum low density lipoprotein. Isolation and characterization of the protein-deficient particles and of its apoproteins. Eur J Biochem 87:475–488Google Scholar
  52. 52.
    Blumberg BS, Dray S, Robinson JC (1962) Antigen polymorphism of a low density beta-lipoprotein allotype in human serum. Nature 194:656–658Google Scholar
  53. 53.
    Bulter R, Brunner E, Morganti G (1974) Contribution to the inheritance of the Ag groups. Vox Sant 26:485–496Google Scholar
  54. 54.
    Berg K (1979) In: Scanu AM, Wissler RW, Getz GS (eds) The Biochemistry of Atherosclerosis: Inherited Lipoprotein Variation and Atherosclerotic Disease. Dekker, New York, pp 419–480Google Scholar
  55. 55.
    Schumaker VN, Robinson MT, Curtiss LK, Butler R, Sparkes RS (1984) Antiapoprotein B monoclonal antibodies detect human low density lipoprotein polymorphism. J Biol Chem 259:6423–6430Google Scholar
  56. 56.
    Young SG, Bertics SJ, Curtiss LK, Casal DC, Witztum JL (1986) Monoclonal antibody MB19 detects genetic polymorphism in human apolipoprotein B. Proc Natl Acad Sci USA 83:1101–1105Google Scholar
  57. 57.
    Wei CF, Chen SH, Yang CY, Marcel YL, Milne RW, Li WH, Sparrow JT, Gotto AM Jr, Chan L (1985) Molecular cloning and expression of partial cDNAs and deduced amino acid sequence of a carboxyl-terminal fragment of human apolipoprotein B-100. Proc Natl Acad Sci USA 82:7265–7269Google Scholar
  58. 58.
    Rapacz J, Haster-Rapacz J, Taylor KM, Checovich WJ, Attie AD (1986) Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. Science 234:1573–1577Google Scholar
  59. 59.
    Ma Y, Schumaker VN, Butler R, Sparkes RS (1987) Two DNA restriction fragment length polymorphisms associated with Ag(t/z) and Ag(g/c) antigenic sites of human apolipoprotein B. Arteriosclerosis 7:301–305Google Scholar
  60. 60.
    Dunning AM, Tikkanen MJ, Ehnholm C, Butler R, Humphries SE (1988) Relationships between DNA and protein polymorphisms of apolipoprotein B. Human Genetics 78:325–329Google Scholar
  61. 61.
    Ma Y, Wang X, Butler R, Schumaker VN (1989) A Bsp 1286 I restriction fragment length polymorphism (RFLP) detects Ag(c/g) locus of human apolipoprotein B. Arteriosclerosis (in press)Google Scholar
  62. 62.
    Hegele RA, Huang LS, Herbert PN, Blum CB, Buring JE, Hennekens CH, Breslow JL (1986) Apolipoprotein B gene DNA polymorphisms associated with myocardial infarction. N Engl J Med 315:1509–1515Google Scholar
  63. 63.
    Jeffreys AJ, Wilson V, Thein SL (1985) Hypervariable “minisatellite” regions in human DNA. Nature 314:67–73Google Scholar
  64. 64.
    Nakamura Y, Leppert M, O'Connell P, Wolff R, Holm T, Culver M, Martin C, Fujimoto E, Hoff M, Kumlin E, White R (1987) Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235:1616–1622Google Scholar
  65. 65.
    Wyman AR, Wolfe LB, Botstein D (1985) Propagation of some human DNA sequences in bacteriophage λ vectors requires mutant Escherichia coli hosts. Proc Natl Acad Sci USA 82:2880–2844Google Scholar
  66. 66.
    Jeffreys AJ, Wilson V, Thein SL (1985) Individual specific “fingerprints” of human DNA. Nature 316:76–79Google Scholar
  67. 67.
    Huang LS, Breslow JL (1987) A unique AT-rich hypervariable minisatellite 3′ to the apoB gene defines a high information restriction fragment length polymorphism. J Biol Chem 262:8952–8955Google Scholar
  68. 68.
    Knott TJ, Wallis SC, Pease RJ, Powell LM, Scott J (1986) A hypervariable region 3′ to the human apolipoprotein B gene. Nucleic Acids Res 14:9215–9216Google Scholar
  69. 69.
    Jenner K, Sidoli A, Ball M, Rodriguez JR, Pagani F, Giudici G, Vergani C, Mann J, Baralle FE, Shoulders CC (1988) Characterization of genetic markers in the 3′ end of the apoB gene and their use in family and population studies. Atherosclerosis 69:39–49Google Scholar
  70. 70.
    Boerwinkle E, Xiong W, Fourest E, Chan L (1989) Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3′ hypervariable region. Proc Natl Acad Sci USA 86:212–216Google Scholar
  71. 71.
    Saiki RK, Bugawan TL, Horn GT, Mullis KB, Erlich HA (1986) Analysis of enzymatically amplified β-globin and HLA-DQa DNA with allele-specific oligonucleotide probes. Nature 324:163–166Google Scholar
  72. 72.
    Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi RG, Horn TT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermstable DNA polymerase. Science 239:498–491Google Scholar
  73. 73.
    Bell GI, Selby MJ, Rutter WJ (1982) The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295:31–35Google Scholar
  74. 74.
    Proudfoot NJ, Gil A, Maniatis T (1982) The structure of the human zetaglobin gene and a closely linked, nearly identical pseudogene. Cell 31:553–563Google Scholar
  75. 75.
    Capon DJ, Chen EY, Levinson AD, Seeburg PH, Goeddel DV (1983) Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 302:33–37Google Scholar
  76. 76.
    Lauer SJ, Walker D, Elshourbagy NA, Reardon CA, Levy-Wilson B, Taylor JM (1988) Two copies of the human apolipoprotein C-I gene are linked closely to the apolipoprotein E gene. J Biol Chem 263:7277–7286Google Scholar
  77. 77.
    Pontes M, Xu X, Graham D, Riley M, Doolittle RF (1987) cDNA sequences of two apolipoproteins from lamprey. Biochemistry 26:1611–1617Google Scholar
  78. 78.
    Chapman MJ, Goldstein S, Mills GL, Leger C (1978) Distribution and characterization of the serum lipoproteins and their apoproteins in the rainbow trout (Salmo gairdnerii). Biochemistry 17:4455–4464Google Scholar
  79. 79.
    Chapman MJ (1980) Animal lipoproteins: chemistry, structure, and comparative aspects. J Lipid Res 21:789–853Google Scholar
  80. 80.
    Babin PJ (1987) Apolipoproteins and the association of egg yolk proteins with plasma high density lipoproteins after ovulation and follicular atresia in the rainbow trout (Salmo gairdneri). J Biol Chem 262:4290–4296Google Scholar
  81. 81.
    Romer AS (1966) Vertebrate Palentology, University of Chicago Press, ChicagoGoogle Scholar
  82. 82.
    Glickman RM, Rogers M, Glickman JN (1986) Apolipoprotein B synthesis by human liver and intestine in vitro. Proc Natl Acad Sci USA 83:5296–5300Google Scholar
  83. 83.
    Marcel YL, Hogue M, Theolis R Jr, Milne RW (1982) Mapping of antigenic determinants of human apolipoprotein B using monoclonal antibodies against low density lipoproteins. J Biol Chem 257:13165–13168Google Scholar
  84. 84.
    Cardin AD, Price CA, Hirose N, Krivanek MA, Blankenship DT, Chao J, Mao SJT (1986) Structural organization of apolipoprotein B-100 of human plasma low density lipoproteins. Comparison to B-48 of chylomicrons and very low density lipoproteins. J Biol Chem 261:16744–16748Google Scholar
  85. 85.
    Young SG, Bertico SJ, Scott TM, Dubois BW, Curtiss LK, Wetztum JL (1986) Parallel expression of the MB19 genetic polymorphism in apoprotein B-100 and apoprotein B-48. Evidence that both apoproteins are products of the same genes. J Biol Chem 261:2995–2998Google Scholar
  86. 86.
    Ludwig EH, Blackhart BD, Pierotti VR, Caiati L, Fortier C, Knott T, Scott J, Mahley RW, Levy-Wilson B, McCarthy BJ (1987) DNA sequence of the human apolipoprotein B gene. DNA 6:363–372Google Scholar
  87. 87.
    Reuben MA, Elovson J (1985) Biosynthesis of apolipoprotein B in rat liver and intestine. Fed Proc 44:1455Google Scholar
  88. 88.
    Crick FHC (1970) Central dogma of molecular biology. Nature 227:561–562Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • L. Chan
    • 1
  1. 1.Departments of Cell Biology and MedicineBaylor College of MedicineHoustonUSA

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