Human haemoglobin: a new paradigm for oxygen binding involving two types of alphabeta contacts.

This review summarizes the most recent state of haemoglobin (Hb) research based on the literature and our own results. In particular, an attempt is made to form a unified picture for haemoglobin function by reconciling the cooperative oxygen binding with the stabilization of the bound dioxygen in aqueous solvent. The HbA molecule contains two types of alphabeta contacts. One type is the alpha1beta2 or alpha2beta1 contacts, called sliding contacts, and these are strongly associated with the cooperative binding of O2 to the alpha2beta2 tetramer. The other type is the alpha1beta1 or alpha2beta2 contacts, called packing contacts, but whose role in Hb function was not clear until quite recently. However, detailed pH-dependence studies of the autoxidation rate of HbO2 have revealed that the alpha1beta1 and alpha2beta2 interfaces are used for controlling the stability of the bound O2. When the alpha1beta1 or alpha2beta2 contact is formed, the beta chain is subjected to a conformational constraint which causes the distal (E7) histidine to be tilted slightly away from the bound dioxygen, preventing the proton-catalysed nucleophilic displacement of O2- from the FeO2 by an entering water molecule. This is one of the most characteristic features of HbO2 stability. Finally we discuss the role of the alpha1beta1 or alpha2beta2 contacts by providing some examples of unstable haemoglobin mutants. These pathological mutations are found mostly on the beta chain, especially in the alpha1beta1 contact regions. In this way, HbA seems to differentiate two types of alphabeta contacts for its functional properties.