Human embryonic, fetal, and adult hemoglobins have different subunit interface strengths. Correlation with lifespan in the red cell

Abstract

The different types of naturally occurring, normal human hemoglobins vary in their tetramer–dimer subunit interface strengths (stabilities) by three orders of magnitude in the liganded (CO or oxy) state. The presence of embryonic ζ‐subunits leads to an average 20‐fold weakening of tetramer–dimer interfaces compared to corresponding hemoglobins containing adult α‐subunits. The dimer–monomer interfaces of these hemoglobins differ by at least 500‐fold in their strengths; such interfaces are weak if they contain ζ‐subunits and exchange with added β‐subunits in the form of β 4 (HbH) significantly faster than do those with α‐subunits. Subunit exchange occurs at the level of the dimer, although tetramer formation reciprocally influences the amount of dimer available for exchange. Competition between subunit types occurs so that pairs of weak embryonic hemoglobins can exchange subunits to form the stronger fetal and adult hemoglobins. The dimer strengths increase in the order Hb Portland‐2 (ζ 2 β 2 ) < Hb Portland‐1 (ζ 2 γ 2 ) ≅ Hb Gower‐1 (ζ 2 ε 2 ) < Hb Gower‐2 (α 2 ε 2 ) < HbF 1 < HbF (α 2 γ 2 ) < HbA 2 (α 2 δ 2 ), i.e., from embryonic to fetal to adult types, representing maturation from weaker to stronger monomer–monomer subunit contacts. This increasing order recapitulates the developmental order in which globins are expressed (embryonic → fetal → adult), suggesting that the intrinsic binding properties of the subunits themselves regarding the strengths of interfaces they form with competing subunits play an important role in the dynamics of protein assemblies and networks.