Hemoglobin Allostery

Structure - Hemoglobin of higher vertebrates is made up of two types of chains, referred to as and . The hemoglobin molecule contains two of each kind of chain, so the whole molecule can be called an 2-2 tetramer. The chains are placed in a roughly tetrahedral arrangement as shown schematically in Figure 7.3. Their primary structures (amino acid sequences) are compared with that of myoglobin in Figure 7.11. The and sequences have considerable similarity to one another and some similarity to that of myoglobin. Essential residues, like the proximal and distal histidine (F8 and E7, respectively), are conserved, and apparently those critical to the tertiary structure are conserved as well, for the myoglobin and hemoglobin chains have very similar tertiary structures.

Chain Interactions - In hemoglobin, the closest and strongest contacts appear to be between and chains, rather than - or - . Figure 7.3 also shows that the heme groups, with their O 2 binding sites, are all close to the surface but not close to one another. Therefore, we cannot seek the source of cooperative binding in anything so unsubtle as direct heme-heme interaction.

Changes on Binding Oxygen - A key to what is happening during oxygenation of hemoglobin can be seen in Figure 7.12. What occurs is mostly a change in the quaternary structure, accompanied by much smaller tertiary structure changes. One / pair rotates and slides with respect to the other, bringing the chains closer together and narrowing a central cavity in the molecule (Figure 7.12b). To a first approximation, the hemoglobin molecule has two states of quaternary structure, one characteristic of the deoxy form and the other favored by the oxy form. The oxy structure has the higher affinity for O 2, and the switch to this state is what accounts for the cooperativity in binding.

Relation to Hill Plot - The Hill plot (Figure 7.9) can be explained in terms of an allosteric shift between two molecular conformations. Wholly deoxygenated hemoglobin molecules are in the deoxy conformation, so addition of oxygen to a solution of such molecules starts the binding along the line corresponding to the weak-binding state. Partial oxygenation favors transition to the strong-binding oxy state. As oxygen is bound, more and more of the remaining available sites are in hemoglobin molecules that have this conformation. Therefore, the binding curve passes over to that for the strong-binding state.

See also: Hill Plots and Cooperativity, Models of Allosteric Activity, Oxygen Binding by Hemoglobin

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