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. 1984 Apr 1;98(4):1256–1264. doi: 10.1083/jcb.98.4.1256

Plasmodium falciparum malaria: association of knobs on the surface of infected erythrocytes with a histidine-rich protein and the erythrocyte skeleton

PMCID: PMC2113211  PMID: 6371019

Abstract

Plasmodium falciparum-infected erythrocytes (RBC) develop surface protrusions (knobs) which consist of electron-dense submembrane cups and the overlying RBC plasma membrane. Knobs mediate cytoadherence to endothelial cells. Falciparum variants exist that lack knobs. Using knobby (K+) and knobless (K-) variants of two strains of P. falciparum, we confirmed Kilejian's original observation that a histidine-rich protein occurred in K+ parasites but not K- variants (Kilejian, A., 1979, Proc. Natl. Acad. Sci. USA, 76:4650-4653; and Kilejian, A., 1980, J. Exp. Med., 151:1534-1538). Two additional histidine-rich proteins of lower molecular weight were synthesized by K+ and K- variants of both strains. We used differential detergent extraction and thin-section electron microscopy to investigate the subcellular location of the histidine-rich protein unique to K+ parasites. Triton X-100, Zwittergent 314, cholic acid, CHAPS, and Triton X-100/0.6 M KCl failed to extract the unique histidine-rich protein. The residues insoluble in these detergents contained the unique histidine-rich protein and electron-dense cups. The protein was extracted by 1% SDS and by 1% Triton X-100/9 M urea. The electron-dense cups were missing from the insoluble residues of these detergents. The electron-dense cups and the unique histidine-rich protein appeared to be associated with the RBC skeleton, particularly RBC protein bands 1, 2, 4.1, and 5. We propose that the unique histidine-rich protein binds to the RBC skeleton to form the electron-dense cup. The electron-dense cup produces knobs by forming focal protrusions of the RBC membrane. These protrusions are the specific points of attachment between infected RBC and endothelium.

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Selected References

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  1. Bonner W. M., Laskey R. A. A film detection method for tritium-labelled proteins and nucleic acids in polyacrylamide gels. Eur J Biochem. 1974 Jul 1;46(1):83–88. doi: 10.1111/j.1432-1033.1974.tb03599.x. [DOI] [PubMed] [Google Scholar]
  2. Desowitz R. S., Miller L. H., Buchanan R. D., Permpanich B. The sites of deep vascular schizogony in Plasmodium coatneyi malaria. Trans R Soc Trop Med Hyg. 1969;63(2):198–202. doi: 10.1016/0035-9203(69)90147-3. [DOI] [PubMed] [Google Scholar]
  3. England B. J., Gunn R. B., Steck T. L. An immunological study of band 3, the anion transport protein of the human red blood cell membrane. Biochim Biophys Acta. 1980 May 29;623(1):171–182. doi: 10.1016/0005-2795(80)90019-7. [DOI] [PubMed] [Google Scholar]
  4. Fairbanks G., Steck T. L., Wallach D. F. Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane. Biochemistry. 1971 Jun 22;10(13):2606–2617. doi: 10.1021/bi00789a030. [DOI] [PubMed] [Google Scholar]
  5. Fremount H. N., Miller L. H. Deep vascular schizogony in Plasmodium fragile: organ distribution and ultrastructure of erythrocytes adherent to vascular endothelium. Am J Trop Med Hyg. 1975 Jan;24(1):1–8. [PubMed] [Google Scholar]
  6. Goldstein J. L., Anderson R. G., Brown M. S. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature. 1979 Jun 21;279(5715):679–685. doi: 10.1038/279679a0. [DOI] [PubMed] [Google Scholar]
  7. Hadley T. J., Leech J. H., Green T. J., Daniel W. A., Wahlgren M., Miller L. H., Howard R. J. A comparison of knobby (K+) and knobless (K-) parasites from two strains of Plasmodium falciparum. Mol Biochem Parasitol. 1983 Nov;9(3):271–278. doi: 10.1016/0166-6851(83)90102-0. [DOI] [PubMed] [Google Scholar]
  8. Kilejian A. Characterization of a protein correlated with the production of knob-like protrusions on membranes of erythrocytes infected with Plasmodium falciparum. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4650–4653. doi: 10.1073/pnas.76.9.4650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kilejian A. Homology between a histidine-rich protein from Plasmodium lophurae and a protein associated with the knob-like protrusions on membranes of erythrocytes infected with Plasmodium falciparum. J Exp Med. 1980 Jun 1;151(6):1534–1538. doi: 10.1084/jem.151.6.1534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  11. Langreth S. G., Reese R. T., Motyl M. R., Trager W. Plasmodium falciparum: loss of knobs on the infected erythrocyte surface after long-term cultivation. Exp Parasitol. 1979 Oct;48(2):213–219. doi: 10.1016/0014-4894(79)90101-2. [DOI] [PubMed] [Google Scholar]
  12. Luse S. A., Miller L. H. Plasmodium falciparum malaria. Ultrastructure of parasitized erythrocytes in cardiac vessels. Am J Trop Med Hyg. 1971 Sep;20(5):655–660. [PubMed] [Google Scholar]
  13. Meryman H. T., Hornblower M. A method for freezing and washing red blood cells using a high glycerol concentration. Transfusion. 1972 May-Jun;12(3):145–156. doi: 10.1111/j.1537-2995.1972.tb00001.x. [DOI] [PubMed] [Google Scholar]
  14. Miller L. H. Distribution of mature trophozoites and schizonts of Plasmodium falciparum in the organs of Aotus trivirgatus, the night monkey. Am J Trop Med Hyg. 1969 Nov;18(6):860–865. doi: 10.4269/ajtmh.1969.18.860. [DOI] [PubMed] [Google Scholar]
  15. Rudzinska M. A., Trager W. The fine structure of trophozoites and gametocytes in Plasmodium coatneyi. J Protozool. 1968 Feb;15(1):73–88. doi: 10.1111/j.1550-7408.1968.tb02091.x. [DOI] [PubMed] [Google Scholar]
  16. Schmidt J. A., Udeinya I. J., Leech J. H., Hay R. J., Aikawa M., Barnwell J., Green I., Miller L. H. Plasmodium falciparum malaria. An amelanotic melanoma cell line bears receptors for the knob ligand on infected erythrocytes. J Clin Invest. 1982 Aug;70(2):379–386. doi: 10.1172/JCI110627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sheetz M. P. Integral membrane protein interaction with Triton cytoskeletons of erythrocytes. Biochim Biophys Acta. 1979 Oct 19;557(1):122–134. doi: 10.1016/0005-2736(79)90095-6. [DOI] [PubMed] [Google Scholar]
  18. Sheetz M. P., Sawyer D. Triton shells of intact erythrocytes. J Supramol Struct. 1978;8(4):399–412. doi: 10.1002/jss.400080403. [DOI] [PubMed] [Google Scholar]
  19. Titani K., Koide A., Hermann J., Ericsson L. H., Kumar S., Wade R. D., Walsh K. A., Neurath H., Fischer E. H. Complete amino acid sequence of rabbit muscle glycogen phosphorylase. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4762–4766. doi: 10.1073/pnas.74.11.4762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  21. Trager W., Rudzinska M. A., Bradbury P. C. The fine structure of Plasmodium falciparum and its host erythrocytes in natural malarial infections in man. Bull World Health Organ. 1966;35(6):883–885. [PMC free article] [PubMed] [Google Scholar]
  22. Udeinya I. J., Miller L. H., McGregor I. A., Jensen J. B. Plasmodium falciparum strain-specific antibody blocks binding of infected erythrocytes to amelanotic melanoma cells. Nature. 1983 Jun 2;303(5916):429–431. doi: 10.1038/303429a0. [DOI] [PubMed] [Google Scholar]
  23. Udeinya I. J., Schmidt J. A., Aikawa M., Miller L. H., Green I. Falciparum malaria-infected erythrocytes specifically bind to cultured human endothelial cells. Science. 1981 Jul 31;213(4507):555–557. doi: 10.1126/science.7017935. [DOI] [PubMed] [Google Scholar]

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