Symmetric interspecies hybrids of mouse and human hemoglobin: Molecular basis of their abnormal oxygen affinity

Rajendra Prasad Roy, Parimala Nacharaju, Ronald L. Nagel, A. Seetharama Acharya

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Interspecies hybrids of HbA and Hb from mouse C57BL/10 [α2MΒ2H and ↠2HΒ2M (H=human, M=mouse)], representing 19 and 27 sequence differences per αΒ dimers (as compared with human αΒ dimer) have been generated in vitro. The efficiency of the assembly of the interspecies hybrids by the alloplex intermediate pathway is about twofold higher than the low-pH-mediated subunit approach. The interspecies hybrids exhibit a cooperative O2 binding. The intrinsic O2 affinity of mouse Hb is slightly lower than HbA, while the 2,3-diphosphoglycerate (DPG) effect is comparable. Interestingly, the interspecies hybrid α2MΒ2H has high O2 affinity (compared to either human or mouse H b), while the interspecies hybrid α2HΒ2M exhibits a very low O2 affinity. These results suggest that the mouse Β chain generates a tetramer with very low oxygen affinity. However, the complementarity of the mouse α and Β chains generates a set of unique interactions that compensate for the low-oxygen-affinity propensity of the mouse Β chain. DPG binds the tetramer in the central cavity formed by the two Β subunits, hence the DPG effects on the interspecies hybrids should be as in the parent molecule. However, the results of the present study demonstrate that the DPG binding pocket is influenced by the nature of the α chain present in the tetramer. The mouse α chain reduces considerably the DPG right shift of the O2 affinity of the human Β-chain containing hybrid. Sequence analysis suggest that perturbations of the α1Β1 (not the α1Β2) are communicated to the DPG binding pocket in the presence of the alien subunit, and are the primary determinant of the ligand binding properties. The results have implications for the design of Hb-based blood substitutes and understanding of the inhibitory potential of mouse α chains in transgenic mouse expressing human ΒS chains.

Original languageEnglish (US)
Pages (from-to)81-88
Number of pages8
JournalJournal of Protein Chemistry
Volume14
Issue number2
DOIs
StatePublished - Feb 1 1995

Keywords

  • DPG
  • blood substitutes
  • Β-chains
  • α-globin

ASJC Scopus subject areas

  • Biochemistry

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