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Restoring allosterism with compensatory mutations in hemoglobin

H W Kim1, T J Shen, D P Sun

  • 1Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.

Proceedings of the National Academy of Sciences of the United States of America
|November 22, 1994
PubMed
Summary
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Compensatory mutations can restore normal oxygen binding in abnormal human hemoglobins (HBs). Replacing tyrosine with aspartic acid at position alpha 42 compensates for defects in Hb Kempsey, a mutant HB.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Abnormal human hemoglobins (HBs) with mutations at the alpha 1 beta 2 interface exhibit altered oxygen affinity and cooperativity.
  • Mutations at beta 99 disrupt intersubunit hydrogen bonds, destabilizing the deoxy quaternary structure of HBs.

Purpose of the Study:

  • To design and investigate compensatory amino acid substitutions to restore allosteric properties in abnormal HBs.
  • To analyze the structural and functional impact of a specific compensatory mutation in Hb Kempsey.

Main Methods:

  • Utilized molecular dynamics to design compensatory mutations.
  • Produced a recombinant double mutant Hb (Asp-beta 99-->Asn and Tyr-alpha 42-->Asp) using Escherichia coli expression.
  • Determined oxygen binding properties and investigated tertiary/quaternary structures using 1H NMR spectroscopy.

Related Experiment Videos

Main Results:

  • The Tyr-alpha 42-->Asp replacement significantly compensated for the functional defect in Hb Kempsey (Asp-beta 99-->Asn).
  • Structural and functional analyses provided insights into the alpha 1 beta 2 subunit interface.
  • Demonstrated the restoration of allosteric properties in the engineered double mutant Hb.

Conclusions:

  • The study highlights the potential of targeted amino acid substitutions to correct functional defects in abnormal HBs.
  • Provides a framework for designing compensatory mutations to treat hemoglobinopathies.
  • Offers insights into the structural basis of allosterism in human hemoglobin.