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

doi:10.1110/ps.072891007

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

Lois R. Manning¹, J. Eric Russell², Julio C. Padovan³, Brian T. Chait³, Anthony Popowicz⁴, Robert S. Manning⁵, and James M. Manning¹

¹ Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA
² Departments of Medicine and Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
³ Laboratory for Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, New York 10021, USA
⁴ Information Technology, The Rockefeller University, New York, New York 10021, USA
⁵ Department of Mathematics, Haverford College, Haverford, Pennsylvania 19041, USA

(RECEIVED March 21, 2007; FINAL REVISION May 22, 2007; ACCEPTED May 23, 2007)

The different types of naturally occurring, normal human hemoglobinsvary in their tetramer–dimer subunit interface strengths(stabilities) by three orders of magnitude in the liganded (COor oxy) state. The presence of embryonic ${zeta}$ -subunits leads toan average 20-fold weakening of tetramer–dimer interfacescompared to corresponding hemoglobins containing adult ${alpha}$ -subunits.The dimer–monomer interfaces of these hemoglobins differby at least 500-fold in their strengths; such interfaces areweak if they contain ${zeta}$ -subunits and exchange with added $beta$ -subunitsin the form of $beta$ ₄ (HbH) significantly faster than do those with ${alpha}$ -subunits. Subunit exchange occurs at the level of the dimer,although tetramer formation reciprocally influences the amountof dimer available for exchange. Competition between subunittypes occurs so that pairs of weak embryonic hemoglobins canexchange subunits to form the stronger fetal and adult hemoglobins.The dimer strengths increase in the order Hb Portland-2 ( ${zeta}$ ₂ $beta$ ₂)< Hb Portland-1 ( ${zeta}$ ₂ ${gamma}$ ₂) ${cong}$ Hb Gower-1 ( ${zeta}$ ₂ ${varepsilon}$ ₂) < Hb Gower-2 ( ${alpha}$ ₂ ${varepsilon}$ ₂)< HbF₁ < HbF ( ${alpha}$ ₂ ${gamma}$ ₂) < HbA₂ ( ${alpha}$ ₂ ${delta}$ ₂), i.e., from embryonicto fetal to adult types, representing maturation from weakerto stronger monomer–monomer subunit contacts. This increasingorder recapitulates the developmental order in which globinsare expressed (embryonic $->$ fetal $->$ adult), suggesting that theintrinsic binding properties of the subunits themselves regardingthe strengths of interfaces they form with competing subunitsplay an important role in the dynamics of protein assembliesand networks.