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.
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
Antonio
A
Tsuneshige
SungIck
S
Park
Takashi
T
Yonetani
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