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Crystallization Mechanisms of Hemoglobin C in the R State

Angela R. Feeling-Taylor ^*, S.-T. Yau , Dimiter N. Petsev , Ronald L. Nagel  ^¶, Rhoda Elison Hirsch ^* ¶ and Peter G. Vekilov 

^* Department of Anatomy and Structural Biology, Albert Einstein College of Medicine and Montefiore Hospital, Comprehensive Sickle Cell Center, The Bronx, New York; Department of Chemical Engineering, University of Houston, Houston, Texas; Department of Physics, Hunter College of the City University of New York, New York; and ^¶ Department of Medicine (Division of Hematology) and Department of Physiology and Biophysics, Albert Einstein College of Medicine and Montefiore Hospital, Comprehensive Sickle Cell Center, The Bronx, New York

Correspondence: Address reprint requests to Peter G. Vekilov, Dept. of Chemical Engineering, University of Houston, Houston, TX 77204-4004. Tel.: 713-743-4315; Fax: 713-743-4323; E-mail: vekilov{at}uh.edu.

Crystallization of the mutated hemoglobin, HbC, which occurs inside red blood cells of patients expressing ß^C-globin and exhibiting the homozygous CC and the heterozygous SC (in which two mutant ß-globins, S and C, are expressed) diseases, is a convenient model for processes underlying numerous condensation diseases. As a first step, we investigated the molecular-level mechanisms of crystallization of this protein from high-concentration phosphate buffer in its stable carbomonoxy form using high-resolution atomic force microscopy. We found that in conditions of equilibrium with the solution, the crystals' surface reconstructs into four-molecule-wide strands along the crystallographic a (or b) axis. However, the crystals do not grow by the alignment of such preformed strands. We found that the crystals grow by the attachment of single molecules to suitable sites on the surface. These sites are located along the edges of new layers generated by two-dimensional nucleation or by screw dislocations. During growth, the steps propagate with random velocities, with the mean being an increasing function of the crystallization driving force. These results show that the crystallization mechanisms of HbC are similar to those found for other proteins. Therefore, strategies developed to control protein crystallization in vitro may be applicable to pathology-related crystallization systems.