Understanding the molecular basis of the high oxygen affinity variant human hemoglobin Coimbra

Author(s)

Jorge, S. E. ^[1] ; Bringas, M. ^{[2, 3]} ; Petruk, A. A. ^{[2, 3]} ; Arrar, M. ^{[2, 3]} ; Marti, M. A. ^{[4, 5]} ; Skaf, M. S. ^[6] ; Costa, F. F. ^[7] ; Capece, L. ^{[2, 3]} ; Sonati, M. F. ^[1] ; Estrin, D. ^{[2, 3]}

Affiliation

^[1] Univ Campinas Unicamp, Sch Med Sci, Dept Clin Pathol, Campinas, SP - Brazil

^[2] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Inorgan Analit & Quim Fis, Buenos Aires, DF - Argentina

^[3] Univ Buenos Aires, CONICET, Inst Quim Fis Mat Medio Ambiente & Energia INQUIM, Buenos Aires, DF - Argentina

^[4] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Buenos Aires, DF - Argentina

^[5] Univ Buenos Aires, CONICET, Inst Quim Biol, Fac Ciencias Exactas & Nat IQUIBICEN, Buenos Aires, DF - Argentina

^[6] State Univ Campinas UNICAMP, Inst Chem, Campinas, SP - Brazil

^[7] Univ Campinas UNICAMP, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil

• Document type: Journal article
• Source: Archives of Biochemistry and Biophysics; v. 637, p. 73-78, JAN 1 2018.
• Web of Science Citations: 2

Abstract

Human hemoglobin (Hb) Coimbra (beta Asp99G1u) is one of the seven beta Asp99 Hb variants described to date. All beta Asp99 substitutions result in increased affinity for O-2 and decreased heme-heme cooperativity and their carriers are clinically characterized by erythrocytocis, caused by tissue hypoxia. Since beta Asp99 plays an important role in the allosteric alpha 1 beta 2 interface and the mutation in lib Coimbra only represents the insertion of a CH2 group in this interface, the present study of Hb Coimbra is important for a better understanding of the global impact of small modifications in this allosteric interface. We carried out functional, kinetic and dynamic characterization of this hemoglobin, focusing on the interpretation of these results in the context of a growth of the position 99 side chain length in the alpha 1 beta 2 interface. Oxygen affinity was evaluated by measuring p50 values in distinct pHs (Bohr effect), and the heme-heme cooperativity was analyzed by determining the Hill coefficient (n), in addition to the effect of the allosteric effectors inositol hexaphosphate (IHP) and 2,3-bisphosphoglyceric acid (2,3-BPG). Computer simulations revealed a stabilization of the R state in the Coimbra variant with respect to the wild type, and consistently, the T-to-R quaternary transition was observed on the nanosecond time scale of classical molecular dynamics simulations. (AU)

• FAPESP's process: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/13710-1 - Structural and functional study of human hemoglobin variants
• Grantee: Susan Elisabeth Domingues Costa Jorge
• Support Opportunities: Scholarships in Brazil - Post-Doctoral