HbC (beta6 Glu->Lys) is the second most common hemoglobin (Hb) variant in the United States and the third most commonly encountered mutant Hb worldwide (Bunn and Forget, 1986). This Hb is present in 2% of African- Americans as HbC trait, CC Disease, and SC Disease (Bunn & Forget, 1986). Although the clinical manifestations between CC Disease and SC Disease are quite different, oxy-state tetragonal Hb crystals are prevalent in the red blood cells of splenectomized CC patients (Hirsch et al., 1985) and SC Disease patients and seem to play a role in the clinical pathogenesis of their respective disease (Nagel et al., 1991; Lawrence et al., 1991). This particular research project will investigate molecular mechanisms of HbC crystallization and factors promoting the crystallization of the oxy liganded form. It is hypothesized that the beta6 Lys substitution promotes a distal ligand-dependent conformational change which in turn promotes crystallization. The thesis project aims (1)to dissect the static and dynamic site-specific conformational differences between the oxy and deoxy forms of HbC compared to the oxy and deoxy forms of HbA using time-resolved site-specific spectroscopy and (2)to define dynamic pathways that lead to HbC crystallization using differential interference microscopy.
| Feeling-Taylor, Angela R; Yau, S-T; Petsev, Dimiter N et al. (2004) Crystallization mechanisms of hemoglobin C in the R state. Biophys J 87:2621-9 |
| Vekilov, Peter G; Feeling-Taylor, Angela; Hirsch, Rhoda Elison (2003) Nucleation and crystal growth of hemoglobins. The case of HbC. Methods Mol Med 82:155-76 |
| Dewan, John C; Feeling-Taylor, Angela; Puius, Yoram A et al. (2002) Structure of mutant human carbonmonoxyhemoglobin C (betaE6K) at 2.0 A resolution. Acta Crystallogr D Biol Crystallogr 58:2038-42 |
| Vekilov, Peter G; Feeling-Taylor, Angela R; Yau, Siu Tung et al. (2002) Solvent entropy contribution to the free energy of protein crystallization. Acta Crystallogr D Biol Crystallogr 58:1611-6 |
