Journal article
The Hb A Variant (β73 Asp→Leu) Disrupts Hb S Polymerization by a Novel Mechanism
Journal of molecular biology, v 362(3), pp 528-538
2006
PMID: 16926024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Polymerization of a 1:1 mixture of hemoglobin S (Hb S) and the artificial mutant HbAβ73Leu produces a dramatic morphological change in the polymer domains in 1.0 M phosphate buffer that are a characteristic feature of polymer formation. Instead of feathery domains with quasi 2-fold symmetry that characterize polymerization of Hb S and all previously known mixtures such as Hb A/S and Hb F/S mixtures, these domains are compact structures of quasi-spherical symmetry. Solubility of Hb S/Aβ73Leu mixtures was similar to that of Hb S/F mixtures. Kinetics of polymerization indicated that homogeneous nucleation rates of Hb S/Aβ73Leu mixtures were the same as those of Hb S/F mixtures, while exponential polymer growth (B) of Hb S/Aβ73Leu mixtures were about three times slower than those of Hb S/F mixtures. Differential interference contrast (DIC) image analysis also showed that fibers in the mixture appear to elongate between three and five times more slowly than in equivalent Hb S/F mixtures by direct measurements of exponential growth of mass of polymer in a domain. We propose that these results of Hb S/Aβ73Leu mixtures arise from a non-productive binding of the hybrid species of this mixture to the end of the growing polymer. This “cap” prohibits growth of polymers, but by nature is temporary, so that the net effect is a lowered growth rate of polymers. Such a cap is consistent with known features of the structure of the Hb S polymer. Domains would be more spherulitic because slower growth provides more opportunity for fiber bending to spread domains from their initial 2-fold symmetry. Moreover, since monomer depletion proceeds more slowly in this mixture, more homogeneous nucleation events occur, and the resulting gel has a far more granular character than normally seen in mixtures of non-polymerizing hemoglobins with Hb S. This mixture is likely to be less stiff than polymerized mixtures of other hybrids such as Hb S with HbF, potentially providing a novel approach to therapy.
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Details
- Title
- The Hb A Variant (β73 Asp→Leu) Disrupts Hb S Polymerization by a Novel Mechanism
- Creators
- Kazuhiko Adachi - The Children's Hospital of Philadelphia, Division of Hematology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAMin Ding - The Children's Hospital of Philadelphia, Division of Hematology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USASaul Surrey - Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USAMaria Rotter - Department of Physics, Drexel University, Philadelphia, PA 19104, USAAlexey Aprelev - Department of Physics, Drexel University, Philadelphia, PA 19104, USAMikhail Zakharov - Department of Physics, Drexel University, Philadelphia, PA 19104, USAWeijun Weng - Department of Physics, Drexel University, Philadelphia, PA 19104, USAFrank A Ferrone - Department of Physics, Drexel University, Philadelphia, PA 19104, USA
- Publication Details
- Journal of molecular biology, v 362(3), pp 528-538
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000240883800012
- Scopus ID
- 2-s2.0-33748096110
- Other Identifier
- 991014877687204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology