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Biochem J. 2004 Jun 15; 380(Pt 3): 889–896.
PMCID: PMC1224201

From the Arctic to fetal life: physiological importance and structural basis of an 'additional' chloride-binding site in haemoglobin.


Haemoglobins from mammals of sub-Arctic and Arctic species, as well as fetal human Hb, are all characterized by a significantly lower Delta H of oxygenation compared with the majority of mammalian haemoglobins from temperate species (exceptions are represented by some cold-resistant species, such as cow, horse and pig). This has been interpreted as an adaptive mechanism of great importance from a physiological point of view. To date, the molecular basis of this thermodynamic characteristic is still not known. In the present study, we show that binding of extra chloride (with respect to adult human Hb) ions to Hb would significantly contribute to lowering the overall heat of oxygenation, thus providing a molecular basis for the low effect of temperature on the oxygenation-deoxygenation cycle. To this aim, the oxygen binding properties of bovine Hb, bear (Ursus arctos) Hb and horse Hb, which are representative of this series of haemoglobins, have been studied with special regard to the effect of heterotropic ligands, such as organic phosphates (namely 2,3-diphosphoglycerate) and chloride. Functional results are consistent with a mechanism for ligand binding that involves an additional binding site for chloride ion. Analysis of computational chemistry results, obtained by the GRID program, further confirm the hypothesis that the reason for the lower Delta H of oxygenation is mainly due to an increase in the number of the oxygen-linked chloride-binding sites.

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  • Coletta M, Clementi ME, Ascenzi P, Petruzzelli R, Condò SG, Giardina B. A comparative study of the temperature dependence of the oxygen-binding properties of mammalian hemoglobins. Eur J Biochem. 1992 Mar 15;204(3):1155–1157. [PubMed]
  • Giardina B, Arevalo F, Clementi ME, Ferrara L, Di Luccia A, Lendaro E, Bellelli A, Condò SG. Evolution of ruminant hemoglobins. Thermodynamic divergence of ox and buffalo hemoglobins. Eur J Biochem. 1992 Mar 1;204(2):509–513. [PubMed]
  • Giardina B, Scatena R, Clementi ME, Cerroni L, Nuutinen M, Brix O, Sletten SN, Castagnola M, Condò SG. Physiological relevance of the overall delta H of oxygen binding to fetal human hemoglobin. J Mol Biol. 1993 Jan 20;229(2):512–516. [PubMed]
  • Clementi ME, Condò SG, Castagnola M, Giardina B. Hemoglobin function under extreme life conditions. Eur J Biochem. 1994 Jul 15;223(2):309–317. [PubMed]
  • di Prisco G, Condò SG, Tamburrini M, Giardina B. Oxygen transport in extreme environments. Trends Biochem Sci. 1991 Dec;16(12):471–474. [PubMed]
  • Brix O, Condò SG, Lazzarino G, Clementi ME, Scatena R, Giardina B. Arctic life adaptation--III. The function of whale (Balaenoptera acutorostrata) hemoglobin. Comp Biochem Physiol B. 1989;94(1):139–142. [PubMed]
  • Brix O, Condò SG, Bardgard A, Tavazzi B, Giardina B. Temperature modulation of oxygen transport in a diving mammal (Balaenoptera acutorostrata). Biochem J. 1990 Oct 15;271(2):509–513. [PMC free article] [PubMed]
  • Tamburrini M, Condò SG, di Prisco G, Giardina B. Adaptation to extreme environments: structure-function relationships in Emperor penguin haemoglobin. J Mol Biol. 1994 Apr 15;237(5):615–621. [PubMed]
  • Giardina B, Brix O, Nuutinen M, el Sherbini S, Bardgard A, Lazzarino G, Condò SG. Arctic adaptation in reindeer. The energy saving of a hemoglobin. FEBS Lett. 1989 Apr 10;247(1):135–138. [PubMed]
  • Giardina B, Condò SG, Petruzzelli R, Bardgard A, Brix O. Thermodynamics of oxygen binding to arctic hemoglobins. The case of reindeer. Biophys Chem. 1990 Aug 31;37(1-3):281–286. [PubMed]
  • Brix O, Bårdgard A, Mathisen S, el Sherbini S, Condò SG, Giardina B. Arctic life adaptation--II. The function of musk ox (Ovibos muschatos) hemoglobin. Comp Biochem Physiol B. 1989;94(1):135–138. [PubMed]
  • Giardina B, Scatena R, Clementi ME, Cerroni L, Nuutinen M, Brix O, Sletten SN, Castagnola M, Condò SG. Physiological relevance of the overall delta H of oxygen binding to fetal human hemoglobin. J Mol Biol. 1993 Jan 20;229(2):512–516. [PubMed]
  • Fronticelli C, Pechik I, Brinigar WS, Kowalczyk J, Gilliland GL. Chloride ion independence of the Bohr effect in a mutant human hemoglobin beta (V1M+H2deleted). J Biol Chem. 1994 Sep 30;269(39):23965–23969. [PubMed]
  • Fronticelli C, Sanna MT, Perez-Alvarado GC, Karavitis M, Lu AL, Brinigar WS. Allosteric modulation by tertiary structure in mammalian hemoglobins. Introduction of the functional characteristics of bovine hemoglobin into human hemoglobin by five amino acid substitutions. J Biol Chem. 1995 Dec 22;270(51):30588–30592. [PubMed]
  • Giardina B, Amiconi G. Measurement of binding of gaseous and nongaseous ligands to hemoglobins by conventional spectrophotometric procedures. Methods Enzymol. 1981;76:417–427. [PubMed]
  • Goodford PJ. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem. 1985 Jul;28(7):849–857. [PubMed]
  • De Rosa MC, Berglund A. A new method for predicting the alignment of flexible molecules and orienting them in a receptor cleft of known structure. J Med Chem. 1998 Feb 26;41(5):691–698. [PubMed]
  • Guenot J, Kollman PA. Molecular dynamics studies of a DNA-binding protein: 2. An evaluation of implicit and explicit solvent models for the molecular dynamics simulation of the Escherichia coli trp repressor. Protein Sci. 1992 Sep;1(9):1185–1205. [PMC free article] [PubMed]
  • Perera Lalith, Darden Thomas A, Pedersen Lee G. Predicted solution structure of zymogen human coagulation FVII. J Comput Chem. 2002 Jan 15;23(1):35–47. [PubMed]
  • Coletta M, Condo SG, Scatena R, Clementi ME, Baroni S, Sletten SN, Brix O, Giardina B. Synergistic modulation by chloride and organic phosphates of hemoglobin from bear (Ursus arctos). J Mol Biol. 1994 Mar 11;236(5):1401–1406. [PubMed]
  • Chiancone E, Norne JE, Forsén S, Antonini E, Wyman J. Nuclear magnetic resonance quadrupole relaxation studies of chloride binding to human oxy- and deoxyhaemoglobin. J Mol Biol. 1972 Oct 14;70(3):675–688. [PubMed]
  • Nigen AM, Manning JM, Alben JO. Oxygen-linked binding sites for inorganic anions to hemoglobin. J Biol Chem. 1980 Jun 25;255(12):5525–5529. [PubMed]
  • Arnone A. X-ray diffraction study of binding of 2,3-diphosphoglycerate to human deoxyhaemoglobin. Nature. 1972 May 19;237(5351):146–149. [PubMed]
  • Pellegrini M, Corda M, Manca L, Olianas A, Sanna MT, Fais A, De Rosa MC, Bertonati C, Masala B, Giardina B. Functional and computer modelling studies of haemoglobin from horse. The haemoglobin system of the Sardinian wild dwarf horse. Eur J Biochem. 2001 Jun;268(11):3313–3320. [PubMed]
  • Wyman J. Regulation in macromolecules as illustrated by haemoglobin. Q Rev Biophys. 1968 May;1(1):35–80. [PubMed]
  • Condò SG, Corda M, Sanna MT, Pellegrini MG, Ruiz MP, Castagnola M, Giardina B. Molecular basis of low-temperature sensitivity in pig hemoglobins. Eur J Biochem. 1992 Oct 15;209(2):773–776. [PubMed]
  • Perutz MF. Species adaptation in a protein molecule. Mol Biol Evol. 1983 Dec;1(1):1–28. [PubMed]

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