Alpha-hemoglobin stabilizing protein: molecular function and clinical correlation

Front Biosci (Landmark Ed). 2010 Jan 1;15:1-11. doi: 10.2741/3601.

Abstract

The discovery of alpha-hemoglobin stabilizing protein (AHSP), a chaperone for free alpha-hemoglobin (alpha-Hb), has provided a satisfactory solution to the perplexing problem of balanced globin levels for Hb production in erythroid cells in the face of a two-fold excess of alpha-globin to beta-globin gene dosage. Unmatched alpha-Hb is unstable and precipitates onto membranes, where the released heme exerts oxidative damages resulting in ineffective erythropoiesis and hemolytic anemia, the underlying causes of pathology in the hereditary anemia of beta-thalassemia. The interaction of alpha-Hb with AHSP involves surfaces normally employed in binding to beta-Hb. However, a conformational change to the AHSP-bound alpha-Hb results in an oxidized heme, but in a pocket that is now less exposed to the outside environment, thereby protecting against both peroxide-induced heme loss and iron-induced redox reaction. Studies in both mice and humans indicate that reduction in AHSP can result in hematological pathology. Conversely, alpha-Hb variants that are compromised in their ability to bind with AHSP produce beta-thalassemia-like symptoms. Disease conditions like some forms of thalassemia that are directly associated with AHSP structural and/or functional defects can now be included within the category of chaperonopathies.

Publication types

  • Review

MeSH terms

  • Animals
  • Blood Proteins / chemistry
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • alpha-Globins / chemistry
  • alpha-Globins / genetics
  • alpha-Globins / metabolism*
  • beta-Globins / chemistry
  • beta-Globins / genetics
  • beta-Globins / metabolism*

Substances

  • AHSP protein, human
  • Blood Proteins
  • Molecular Chaperones
  • alpha-Globins
  • beta-Globins