title: The global allostery model of hemoglobin: an allosteric mechanism involving homotropic and heterotropic interactions.
abstract: Studies of the allosteric mechanism of hemoglobin (Hb) have evolved from phenomenological descriptions to structure-based molecular mechanisms, as the molecular structures of Hb in deoxy and ligated states have been elucidated. The MWC two-state concerted model has been the widely accepted as the most plausible of the allosteric mechanisms of Hb. It assumes that the O2-affinity of Hb is regulated/controlled primarily by the T/R quaternary structural transition and that heterotropic effectors bind preferentially to T (deoxy) Hb to shift the T/R allosteric equilibrium toward the T state. However, recent more comprehensive O2-binding measurements of Hb have revealed a new mechanism, the Global Allostery model. It describes that the O2-affinity and the cooperativity are modulated in greater extents and the Bohr effect is generated primarily by the tertiary structural changes in both T (deoxy) and R (ligated) states of Hb. Differential interactions of heterotropic allosteric effectors with both T (deoxy) and R (ligated) states of Hb induce these tertiary structural changes. The X-ray structure of a complex of R (ligated) Hb with BZF, a potent heterotropic effector, has revealed the stereo-chemical influence of these effectors on the structure of R (ligated) Hb, resulting in the reduction of the ligand affinity in R (ligated) Hb. This model stresses the fundamental importance of the heterotropic interactions in regulation/control of the functionality of Hb. They alter the tertiary structures of both T (deoxy) and R (oxy) Hb, leading to large-scale modulations of the O2 affinity (KT and KR), and consequently the cooperativity (KR/KT) and the Bohr effect (delta P50/delta pH) from a global viewpoint of allostery in Hb.
authors.affiliation: Department of Biochemistry and Biophysics, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA 19104-6059, USA. yonetant@mail.med.upenn.edu
authors.forename: Takashi
authors.initials: T
authors.lastname: Yonetani
authors.forename: Antonio
authors.initials: A
authors.lastname: Tsuneshige
mesh_terms: D000328:Adult; D000495:Allosteric Site; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010108:Oxyhemoglobins / Q000737:chemistry; D020836:Protein Structure, Quaternary
chemical_list: D006454:Hemoglobins; D010108:Oxyhemoglobins