title: Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin.
abstract: 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.
authors.affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Feng
authors.forename: David A
authors.initials: DA
authors.lastname: Gell
authors.forename: Suiping
authors.initials: S
authors.lastname: Zhou
authors.forename: Lichuan
authors.initials: L
authors.lastname: Gu
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: Jianqing
authors.initials: J
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Nieng
authors.initials: N
authors.lastname: Yan
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Anne M
authors.initials: AM
authors.lastname: Rich
authors.forename: Robert S
authors.initials: RS
authors.lastname: Armstrong
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D018360:Crystallography, X-Ray; D004795:Enzyme Stability / Q000502:physiology; D006441:Hemoglobin A / Q000737:chemistry* / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D046911:Macromolecular Substances / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010108:Oxyhemoglobins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D034421:Sus scrofa
chemical_list: C468768:AHSP protein, human; D001798:Blood Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D010108:Oxyhemoglobins; D021122:Protein Subunits; D006639:Histidine; D006441:Hemoglobin A; C029774:oxyhemoglobin A; D007501:Iron