Heterotropic effectors control the hemoglobin function by interacting with its T and R states--a new view on the principle of allostery.
Careful analyses of precise oxygenation curves of hemoglobin (Hb) clearly indicate that, contrary to the common belief, allosteric effectors exert a dramatic control of the oxygenation characteristics of the protein by binding not only to the T (unligated), but also to the R (ligated) state, in a process that is proton-driven and involves proton uptake. The most striking functional changes were obtained when the allosteric effectors were bound to the fully ligated Hb: the oxygen affinity decreased dramatically, Bohr effect was enhanced, and cooperativity of oxygen ligation was almost absent, emulating a Root effect-like behavior. However, structural analysis, such as Cys beta 93 sulfhydryl reactivity and ultraviolet circular dichroism, confirmed that the ligated Hb was in fact in the R state, despite its extremely low affinity state features. These findings provide a new global view for allosteric interactions and invoke for a modern interpretation of the role of allosteric effectors and a reformulation of the Monod-Wyman-Changeaux model for control of allosteric systems, and other complementary models as well.
Tsuneshige
Antonio
A
Department of Biochemistry and Biophysics and The Johnson Research Foundation, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA. ants@mail.med.upenn.edu
Park
SungIck
S
Yonetani
Takashi
T
D000328:Adult; D000494:Allosteric Regulation / Q000502:physiology; D000495:Allosteric Site; D001629:Bezafibrate / Q000737:chemistry / Q000494:pharmacology; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D006441:Hemoglobin A / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010100:Oxygen / Q000097:blood* / Q000378:metabolism; D010833:Phytic Acid / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation
D002712:Chlorides; D010833:Phytic Acid; D002248:Carbon Monoxide; D006441:Hemoglobin A; D003545:Cysteine; D010100:Oxygen; D001629:Bezafibrate