title: Energetic differences at the subunit interfaces of normal human hemoglobins correlate with their developmental profile.
abstract: A previously unrecognized function of normal human hemoglobins occurring during protein assembly is described, i.e. self-regulation of subunit pairings and their durations arising from the variable strengths of their subunit interactions. Although many mutant human hemoglobins are known to have altered subunit interface strengths, those of the normal embryonic, fetal, and adult human hemoglobins have not been considered to differ significantly. However, in a comprehensive study of both types of subunit interfaces of seven of the eight normal oxy human hemoglobins, we found that the strengths, i.e., the free energies of the tetramer-dimer interfaces, contrary to previous reports, differ by 3 orders of magnitude and display an undulating profile similar to the transitions ("switches") of various globin subunit types over time. The dimer interface strengths are also variable and correlate linearly with their developmental profile. Embryonic hemoglobins are the weakest; fetal hemoglobin is of intermediate strength, and adult hemoglobins are the strongest. The pattern also correlates generally with their different O(2) affinities and responses to allosteric regulatory molecules. Acetylation of fetal hemoglobin weakens its unusually strong subunit interactions and occurs progressively as its level of expression diminishes and adult hemoglobin A formation begins; a causal relationship is suggested. The relative contributions of globin gene order and competition among subunits due to differences in their interface strengths were found to be complementary and establish a connection among genetics, thermodynamics, and development.
authors: Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Lois R
authors: LR
authors: Manning
authors: J Eric
authors: JE
authors: Russell
authors: Anthony M
authors: AM
authors: Popowicz
authors: Robert S
authors: RS
authors: Manning
authors: Julio C
authors: JC
authors: Padovan
authors: James M
authors: JM
authors: Manning
mesh_terms: D000328:Adult; D000818:Animals; D018507:Gene Expression Regulation, Developmental; D006454:Hemoglobins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D006454:Hemoglobins; D018398:Homeodomain Proteins; D021122:Protein Subunits; D010100:Oxygen