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Abstract
Human hemoglobin (Hb), which is an α2β2 tetramer and binds four O2 molecules, changes its O2-affinity from low to high as an increase of bound O2, that is characterized by ‘cooperativity’. This property is indispensable for its function of O2 transfer from a lung to tissues and is accounted for in terms of T/R quaternary structure change, assuming the presence of a strain on the Fe-histidine (His) bond in the T state caused by the formation of hydrogen bonds at the subunit interfaces. However, the difference between the α and β subunits has been neglected. To investigate the different roles of the Fe-His(F8) bonds in the α and β subunits, we investigated cavity mutant Hbs in which the Fe-His(F8) in either α or β subunits was replaced by Fe-imidazole and F8-glycine. Thus, in cavity mutant Hbs, the movement of Fe upon O2-binding is detached from the movement of the F-helix, which is supposed to play a role of communication. Recombinant Hb (rHb)(αH87G), in which only the Fe-His in the α subunits is replaced by Fe-imidazole, showed a biphasic O2-binding with no cooperativity, indicating the coexistence of two independent hemes with different O2-affinities. In contrast, rHb(βH92G), in which only the Fe-His in the β subunits is replaced by Fe-imidazole, gave a simple high-affinity O2-binding curve with no cooperativity. Resonance Raman, 1H NMR, and near-UV circular dichroism measurements revealed that the quaternary structure change did not occur upon O2-binding to rHb(αH87G), but it did partially occur with O2-binding to rHb(βH92G). The quaternary structure of rHb(αH87G) appears to be frozen in T while its tertiary structure is changeable. Thus, the absence of the Fe-His bond in the α subunit inhibits the T to R quaternary structure change upon O2-binding, but its absence in the β subunit simply enhances the O2-affinity of α subunit.
Highlights
IntroductionOxygen molecules incorporated are transported to tissues by hemoglobin (Hb) in blood and are mostly reduced to water by cytochrome oxidase at mitochondria in order to synthesize ATP, that is, to create energy [1,2]
We uptake O2 in a lung through breathing
The present results indicate that the detachment of a heme from F-helix in the α subunits inhibits the quaternary structure change from T to R upon ligand binding, being compatible with the results from hybrid Hbs, and that a similar detachment in the β subunits enhances the O2 affinity of the α subunit, which was not previously reported
Summary
Oxygen molecules incorporated are transported to tissues by hemoglobin (Hb) in blood and are mostly reduced to water by cytochrome oxidase at mitochondria in order to synthesize ATP, that is, to create energy [1,2]. This activity is vital for life maintenance. The O2 binding/release by heme is based on chemical equilibrium. The concentrations of O2-bound forms are proportional to partial pressure of O2 in the absence of interactions among O2-binding sites. Nonlinear dependence of the concentrations of O2-bound forms on partial pressure of O2 is desirable [3]
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