title: Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem.
abstract: The synthesis of haemoglobin A (HbA) is exquisitely coordinated during erythrocyte development to prevent damaging effects from individual alpha- and beta-subunits. The alpha-haemoglobin-stabilizing protein (AHSP) binds alpha-haemoglobin (alphaHb), inhibits the ability of alphaHb to generate reactive oxygen species and prevents its precipitation on exposure to oxidant stress. The structure of AHSP bound to ferrous alphaHb is thought to represent a transitional complex through which alphaHb is converted to a non-reactive, hexacoordinate ferric form. Here we report the crystal structure of this ferric alphaHb-AHSP complex at 2.4 A resolution. Our findings reveal a striking bis-histidyl configuration in which both the proximal and the distal histidines coordinate the haem iron atom. To attain this unusual conformation, segments of alphaHb undergo drastic structural rearrangements, including the repositioning of several alpha-helices. Moreover, conversion to the ferric bis-histidine configuration strongly and specifically inhibits redox chemistry catalysis and haem loss from alphaHb. The observed structural changes, which impair the chemical reactivity of haem iron, explain how AHSP stabilizes alphaHb and prevents its damaging effects in cells.
authors.affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Feng
authors.forename: Suiping
authors.initials: S
authors.lastname: Zhou
authors.forename: Lichuan
authors.initials: L
authors.lastname: Gu
authors.forename: David A
authors.initials: DA
authors.lastname: Gell
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D001798:Blood Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006418:Heme / Q000378:metabolism*; D006441:Hemoglobin A / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010108:Oxyhemoglobins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D018832:Molecular Chaperones; D010108:Oxyhemoglobins; D017382:Reactive Oxygen Species; D006418:Heme; D006441:Hemoglobin A