Abstract
The polymerization of sickle hemoglobin occurs by the same mechanisms in solutions and in cells, and involves the formation of 14 stranded fibers from hemoglobin molecules which have assumed a deoxy quaternary structure. The fibers form via two types of highly concentration-dependent nucleation processes: homogeneous nucleation in solutions with hemoglobin activity above a critical activity, and heterogeneous nucleation in similarly supersaturated solutions which also contain hemoglobin polymers. The latter pathway is dominant, and creates polymer arrays called domains. The individual polymers bend, but also cross-link, and the resulting mass behaves as a solid. The concentration of polymerized hemoglobin increases exponentially unless clamped by rate limiting effects such as oxygen delivery.
Article PDF
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.Avoid common mistakes on your manuscript.
Literature
Basak, S., Ferrone, F. A., and Wang, J. T., Kinetics of domain formation by sickle hemoglobin polymers. Biophys. J.54 (1988) 829–843.
Beach, D. A., Bustamante, C., Wells, K. S., and Foucar, K. M., Differential polarization imaging. III. Theory confirmation. Patterns of polymerization of hemoglobin S in red blood cells. Biophys. J.53 (1988) 449–456.
Bishop, M. F., and Ferrone, F. A., Kinetics of nucleation controlled polymerization: a perturbation treatment for use with a secondary pathway. Biophys. J.46 (1984) 631–644.
Briehl, R. W., Solid-like behaviour of unsheared sickle hemoglobin gels and the effects of shear. Nature228 (1980) 622–624.
Briehl, R. W., Mann, E. S., and Josephs, R., Length distributions of hemoglobin S fibers. J. molec. Biol.211 (1990) 693–698.
Cho, M. R., and Ferrone, F. A., Monomer diffusion into polymer domains in sickle hemoglobin. Biophys. J.58 (1990) 1067–1073.
Cho, M. R., and Ferrone, F. A., Monomer diffusion and polymer alignment in domains of sickle hemoglobin. Biophys. J.63 (1991) 205–214.
Dykes, G., Crepeau, R. H., and Edelstein, S. J., Three dimensional reconstruction of the fibres of sickle cell hemoglobin. Nature272 (1978) 506–510.
Dykes, G. W., Crepeau, R. H., and Edelstein, S. J., Three dimensional reconstruction of 14-filament fibers of hemoglobin S. J. molec. Biol.130 (1979) 451–472.
Eaton, W. A., and Hofrichter, J., Hemoglobin S gelation and sickle cell disease. Blood70 (1987) 1245–1266.
Eaton, W. A., and Hofrichter, J., Sickle cell hemoglobin polymerization. Adv. Protein Chem.40 (1990) 63–280.
Ferrone, F. A., Hofrichter, J., and Eaton, W. A., Kinetics of sickle hemoglobin polymerization II: a double nucleation mechanism. J. molec. Biol.183 (1985) 611–631.
Ferrone, F. A., Hofrichter, J., and Eaton, W. A., Kinetics of sickle hemoglobin polymerization I: studies using temperature-jump and laser photolysis techniques. J. molec. Biol.183 (1985) 591–610.
Ferrone, F. A., Hofrichter, J., Sunshine, H., and Eaton, W. A., Kinetic studies on photolysis-induced gelation of sickle cell hemoglobin suggest a new mechanism. Biophys. J.32 (1980) 361–377.
Ferrone, F. A., Cho, M. R., and Bishop, M. F., Can a successful mechanism for HbS gelation predict sickle cell crises? in: Approaches to the Therapy of Sickle Cell Anemia, pp. 53–66. Eds Y. Beuzard, S. Charache and F. Galacteros. INSERM, Paris 1986.
Gill, S., Spokane, R., Benedict, R. C., Fall, L., and Wyman, J., Ligand-linked phase equilibria of sickle cell hemoglobin. J. molec. Biol.140 (1980) 299–312.
Goldberg, M. A., Lalos, A. T., and Bunn, H. F., The effect of erythrocyte membrane preparations on the polymerization of sickle hemoglobin. J. biol. Chem.256 (1981) 193–197.
Hofrichter, J., Kinetics of sickle hemoglobin polymerization. III. Nucleation rates determined from stochastic fluctuations in polymerization progress curves. J. molec. Biol.189 (1986) 553–571.
Hofrichter, J., Ross, P. D., and Eaton, W. A., A physical description of hemoglobin S gelation, in: Proceedings of the Symposium on Molecular and Cellular Aspects of Sickle Cell Disease, pp. 185–224. Eds J. I. Hercules, G. L. Cottan, M. R. Waterman and A. N. Schechter. DHEW publication NIH 76-1007, 1976.
Hofrichter, J., Ross, P. D., and Eaton, W. A., Supersaturation in sickle cell hemoglobin solutions. Proc. natl Acad. Sci. USA73 (1976) 3035–3039.
Kam, Z., and Hofrichter, J., Quasi-elastic laser light scattering from solutions and gels of hemoglobin S. Biophys. J.50 (1986) 1015–1020.
Lonsdorfer, J., Bogui, P., Otayeck, A., Bursaux, E., Poyart, C., and Cabannes, R., Cardiorespiratory adjustments in chronic sickle cell anemia. Bull. Eur. Physiopath. Respir.19 (1983) 339.
Mackie, L. H., and Hochmuth, R. M., The influence of oxygen tension, temperature and hemoglobin concentration on the rheologic properties of sickle erythrocytes. Blood76 (1990) 1256–1261.
Mickols, W., Maestre, M. F., Tinoco, I., and Embury, S. H., Visualization of oriented hemoglobin S in individual erythrocytes by differential extinction of polarized light. Proc. natl Acad. Sci. USA82 (1985) 6527–6531.
Minton, A. P., The effect of volume occupancy upon the thermodynamic activity of proteins: Some biological consequences. Molec. Cell Biochem.55 (1983) 119–140.
Monod, J. C., Wyman, J., and Changeux, J. P., On the nature of allosteric transitions: a plausible model. J. molec. Biol.12 (1965) 88–118.
Mozzarelli, A., Hofrichter, J., and Eaton, W. A., Delay time of hemoglobin S polymerization prevents most cells from sickling. Science237 (1987) 500–506.
Mozzarelli, A., Rivetti, C., Rossi, G. L., Henry, E. R., and Eaton, W. A., Crystals of hemoglobin with the T quarternary structure bind oxygen noncooperatively with no Bohr effect. Nature351 (1991) 416–419.
Nash, G., Johnson, C. J., and Meiselman, H. J., Influence of oxygen tension on the viscoelastic behavior of red blood cells in sickle cell disease. Blood67 (1986) 110–118.
Nash, G. B., Red cell mechanics: what changes are needed to adversely affect in vivo circulation. Biorheology28 (1991) 231–239.
Pennelly, R. R., and Noble, R. W., Functional identity of hemoglobins S and A in the absence of polymerization, in: Biochemical and Clinical Aspects of Hemoglobin Abnormalities, pp. 401–411. Ed. W. S. Caughey. Academic Press, New York 1978.
Poillon, W. N., Robinson, M. D., and Kim, B. C., Deoxygenated sickle hemoglobin: modulation of its solubility by 2,3-diphosphoglycerate and other allosteric polyanions. J. biol. Chem.260 (1985) 13897–13900.
Samuel, R. E., Salmon, E. D., and Briehl, R. W., Nucleation and growth of fibres and gel formation in sickle cell hemoglobin. Nature345 (1990) 833–835.
Schechter, A. N., Noguchi, C. T., and Rodgers, G. P., Sickle cell disease, in: Molecular Basis of Blood Diseases, pp. 179–218. Eds G. Stamatoyannopoulos, A. W. Nienhuis, P. Leder and P. W. Majerus. Saunders, Philadelphia, PA 1987.
Sunshine, H. R., Hofrichter, J., and Eaton, W. A., Gelation of sickle cell hemoglobin in mixtures with normal adult and fetal hemoglobins. J. molec. Biol.133 (1979) 435–467.
Sunshine, H. R., Hofrichter, J., Ferrone, F. A., and Eaton, W. A., Oxygen binding by sickle cell hemoglobin polymers. J. molec. Biol.158 (1982) 251–273.
Watowich, S. J., Gross, L. J., and Josephs, R. J., Intramolecular contacts within sickle hemoglobin fibers. J. molec. Biol.209 (1989) 821–828.
Wellems, T. E., Vassar, R. J., and Josephs, R., Polymorphic assemblies of double strands of sickle cell hemoglobin. Manifold pathways of deoxyhemoglobin S crystallization. J. molec. biol.13 (1981) 1011–1026.
White, J. G., and Heagan, B.. The fine structure of cell free sickled hemoglobin. Am. J. Path.58 (1970) 1–17.
Wishner, B. C., Ward, K. B., Lattman, E. E., and Love, W. E., Crystal structure of sickle-cell deoxyhemoglobin at 5 Å resolution. J. molec. Biol.98 (1975) 179–194.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ferrone, F.A. The polymerization of sickle hemoglobin in solutions and cells. Experientia 49, 110–117 (1993). https://doi.org/10.1007/BF01989414
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01989414