Hemoglobin subunit interactions

Manning JM et aJ Normal and abnormal protein subunit interactions in hemoglobins.] Biol Chem 1998 273 19359-Mario N, Baudin B, Giboudeau J Qualitative and quantitative analysis of hemoglobin variants by capillary isoelectric focusing. J Chromatogr B Biomed Sci Appl 1998 706 123-Reed W, Vichinsky EP New considerations in the treatment of sickle cell disease. Annu Rev Med 1998 49 46l. 

FIGURE 5-8 Dominant interactions between hemoglobin subunits. 

Sigmoid kinetic behavior generally reflects cooperative interactions between protein subunits. In other words, changes in the structure of one subunit are translated into structural changes in adjacent subunits, an effect mediated by noncovalent interactions at the interface between subunits. The principles are particularly well illustrated by a nonenzyme 02 binding to hemoglobin. Sigmoid kinetic behavior is explained by the concerted and sequential models for subunit interactions (see Fig. 5-15). 

F. C. Mills, M. L. Johnson, and J. K. Akers, Oxygenation-linked subunit interactions in human hemoglobin Experimental studies on the concentration dependence of oxygenation curves, Biochemistry 15, 5350 (1976). 

Hemoglobin has been a favorite protein molecule for designing and testing various models of the molecular basis of subunit interactions in multisubunit proteins. In the 1960s, two mechanisms were advanced to account for the sigmoidal nature of the oxygen binding curve for Hb A, one proposed by Monod et al. (1965) based on a... 

In Hb Little Rock, we have a j3143His— Gln replacement. The effect of this replacement is that DPG cannot be bound by the Hb Little Rock molecule, which therefore results in the predominance of the R forms of the hemoglobin. In general, then, amino acid substitutions in the high oxygen affinity hemoglobins interfere with the subunit interactions in such a way that either T forms are destabilized or R forms are stabilized. 

In conclusion, the interactions between the subunits of hemoglobin allow the release of oxygen to be fine-tuned to physiological needs. The allosteric effectors BPG, H+ and C02 all lower the affinity of hemoglobin for oxygen by increasing the strength of the subunit interactions. 

In hemoglobin, the interactions between the subunits are known under the general term of allosteric properties and are of great physiological importance. They determine the cooperative binding of O2. In the deoxy form, the iron atom of each heme is in a high-spin (S =2) five-coordinate iron(II) state and lies about 0.5 A out of the heme plane in the direction of the proximal histidine [12]. The Fe-N(imida2ole) bond vector has 10° tilt off the heme normal. 

J. M. Manning, A. Dumoulin, X. Lee, et al. Normal and abnormal protein subunit interactions in hemoglobins. Journal of Biological Chemistry 273, 19359(1998). 

The quaternary structure observed m the deoxy form of hemoglobin is often referred to as the T (for tense) state because it is quite constrained by subunit—subunit interactions. The quaternary structure of the fully oxygenated form is referred to as the R (for relaxed) state. In light of the observation that the R form of hemoglobin is less constrained, the tense and relaxed designations seem particularly apt. Importantly, in the R state, the... 

Subunit interactions in the quaternary structure are vital for allosteric control of 02 binding by hemoglobin and this can be affected by mutations of residues in the subunit interfaces. The result is usually an abnormal 02 affinity. 

Finally, protein chains interact with each other as subunits associate to make a functional species. For example, hemoglobin, the mammalian oxygen carrier, contains two each of two different subunits. The ability of hemoglobin to deliver oxygen to the tissues is dependent on the association of these subunits. Interaction of proteins to form a multimer composed of several subunits is termed the protein s quaternary structure. Quaternary structure is often very important in determining the regulatory properties of a protein. 

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