Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin

Cell. 2004 Nov 24;119(5):629-40. doi: 10.1016/j.cell.2004.11.025.


Hemoglobin A (HbA), the oxygen delivery system in humans, comprises two alpha and two beta subunits. Free alpha-hemoglobin (alphaHb) is unstable, and its precipitation contributes to the pathophysiology of beta thalassemia. In erythrocytes, the alpha-hemoglobin stabilizing protein (AHSP) binds alphaHb and inhibits its precipitation. The crystal structure of AHSP bound to Fe(II)-alphaHb reveals that AHSP specifically recognizes the G and H helices of alphaHb through a hydrophobic interface that largely recapitulates the alpha1-beta1 interface of hemoglobin. The AHSP-alphaHb interactions are extensive but suboptimal, explaining why beta-hemoglobin can competitively displace AHSP to form HbA. Remarkably, the Fe(II)-heme group in AHSP bound alphaHb is coordinated by the distal but not the proximal histidine. Importantly, binding to AHSP facilitates the conversion of oxy-alphaHb to a deoxygenated, oxidized [Fe(III)], nonreactive form in which all six coordinate positions are occupied. These observations reveal the molecular mechanisms by which AHSP stabilizes free alphaHb.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Blood Proteins / chemistry*
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Cattle
  • Crystallography, X-Ray
  • Enzyme Stability / physiology
  • Hemoglobin A / chemistry*
  • Hemoglobin A / metabolism*
  • Histidine / metabolism
  • Humans
  • Iron / metabolism
  • Macromolecular Substances / chemistry
  • Mice
  • Models, Molecular
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Oxyhemoglobins / metabolism
  • Protein Binding / physiology
  • Protein Structure, Tertiary / physiology
  • Protein Subunits / metabolism
  • Rats
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Sus scrofa


  • AHSP protein, human
  • Blood Proteins
  • Macromolecular Substances
  • Molecular Chaperones
  • Oxyhemoglobins
  • Protein Subunits
  • Histidine
  • Hemoglobin A
  • oxyhemoglobin A
  • Iron

Associated data

  • PDB/1XZY
  • PDB/1Y01