Proton nuclear magnetic resonance investigation of structural changes associated with cooperative oxygenation of human adult hemoglobin

Viggiano, G; Ho, Chien

doi:10.1073/pnas.76.8.3673

Cited by 76 publications

(37 citation statements)

References 19 publications

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“…(ii) We constrained the ratio of probabilities of binding oxygen by the a and 8 chains to be 1.0 ± 0.05 in the range between zero and half-saturation of tetramers, in accord with the results of NMR determinations (34,35). xiii) At pH 7.4 the change in quaternary structure with fractional saturation of tetramers Y4 was constrained to be linear to within 5% between Y4 = 0 and Y4 = 0.5, in accord with results of NMR determinations (34).…”

Section: (31)supporting

confidence: 48%

“…xiii) At pH 7.4 the change in quaternary structure with fractional saturation of tetramers Y4 was constrained to be linear to within 5% between Y4 = 0 and Y4 = 0.5, in accord with results of NMR determinations (34).…”

Section: (31)mentioning

confidence: 54%

“…1-4. A number of these can be tested-e.g., by extended NMR studies of the fractional saturation of a and (3chains (34,35) and the fractional quaternary structure change (33,34). Within the framework provided by this model, a more rigorous set of rules may be incorporated for the pairwise subunit interactions.…”

Section: Resultsmentioning

confidence: 99%

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A quantitative model for the cooperative mechanism of human hemoglobin.

Johnson¹,

Turner²,

Ackers³

1984

Proc. Natl. Acad. Sci. U.S.A.

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A quantitative model has been developed for the cooperative oxygenation of human hemoglobin. The model correlates the structural and energetic features of ligandlinked subunit interactions within the tetrameric molecule and the coupling of these interactions to the binding of oxygen and Least squares minimization was used to evaluate from these data the free energies for the various processes. A special feature of the model lies in the synchronization of Bohr proton release with changes in quaternary structure. This leads to the striking prediction that a major fraction (as much as 30%) of tetramers are in the oxy quaternary structure after the first oxygen is bound. The model provides a rationale for the essential features of regulatory energy control, and it defines several kinds of additional information that are needed for a more complete understanding of the hemoglobin mechanism.Cooperative oxygen binding in human hemoglobin is a classic example of the problem of relating structure to function in biological macromolecules. The appeal of hemoglobin as a system in which to study this problem stems in part from the facts that (i) the tetrameric molecule exhibits self-regulation by changing its affinity for oxygen at the four successive binding steps, (ii) structurally the hemoglobin molecule is relatively simple compared with other self-regulating macromolecular assemblies, and (iii) hemoglobin operates essentially as an equilibrium thermodynamic system in vivo, so that the biological processes of interest are purely thermodynamic in character-e.g., the changes in Gibbs free energies of the stepwise binding reactions. The structure-function problem is thus one of relating structural changes to thermodynamic changes and of understanding how these processes are influenced by interactions of the protein with small "regulatory" molecules such as protons, Cl-, C02, and organic phosphates.Much of the necessary structural information regarding the tertiary and quaternary changes that accompany oxygenation has been provided by extensive x-ray crystallographic studies, beginning with the classic work of Perutz and colleagues (1). The crystallographic results (cf. ref. 2) have been supplemented by structural studies in solution by extended x-ray absorption fine structure (3), resonance Raman (4), and NMR (5) spectroscopy.Equally important to an understanding of the cooperative mechanism is a knowledge of the sources and manifestations offree energy change that accompany the functional cycle of oxygenation-deoxygenation. We have carried out an extensive series of studies over the last 10 years aimed at resolving energetic aspects of the hemoglobin mechanism and of correlating the thermodynamic and structural information (cf. refs. 6-15). These studies, and work from other laboratories, have resulted in findings that impose stringent constraints on the nature of interactions responsible for cooperativity. In this paper we present a statistical thermodynamic model that incorporates these recent findings. (For other...

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Section: (31)supporting

confidence: 48%

Section: (31)mentioning

confidence: 54%

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A quantitative model for the cooperative mechanism of human hemoglobin.

Johnson¹,

Turner²,

Ackers³

1984

Proc. Natl. Acad. Sci. U.S.A.

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“…4). Also, it has been suggested that cooperativity can occur in the absence of a change in quaternary structure (14,39). Experimental results indicate that such a contribution to the cooperative oxygen binding, if it exists, is not important.…”

Section: Formulation Of the Modelmentioning

confidence: 67%

“…Spectroscopic studies of probes sensitive to specific changes are providing valuable information for testing models of cooperativity; an example is the attempt to distinguish between aand (3chain oxygenation by NMR (14,15) and by optical measurements (16). Highly accurate equilibrium measurements for oxygen binding in hemoglobin have been made under carefully controlled conditions (17,18); this removes some of the uncertainties present in the Roughton-Lyster data (19) on which the original fits were based.…”

mentioning

confidence: 99%

Structure-specific model of hemoglobin cooperativity.

Lee¹,

Karplus²

1983

Proc. Natl. Acad. Sci. U.S.A.

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A generalization of the Szabo-Karplus statistical mechanical model for hemoglobin cooperativity is formulated. The model fits the available thermodynamic and spectroscopic data with assumptions that are consistent with structural results and empirical energy function calculations. It provides a mechanism of hemoglobin cooperativity that is a generalization of the proposals of Monod, Wyman, and Changeux and of Perutz. The role of nonsalt-bridge related sources of constraints on ligand affinity and the mode of salt-bridge coupling to tertiary-quaternary structural changes are examined within the framework of the model. Analysis of proton release data for a range of pH values indicates that a pH-independent part of cooperativity must be present. The pH dependence of the first and last Adair constants point to partial linkage of salt bridges to ligation in the deoxy state and to a destabilized intra-13chain salt bridge in the unliganded oxy state.Hemoglobin has long been regarded as the prototype system for the investigation of cooperativity in macromolecules. The essential aim of such studies is to determine the detailed relationship between structural changes induced by ligation and the thermodynamic and kinetic manifestation of cooperativity. The x-ray structures of various hemoglobins solved by Perutz and his collaborators (1) have demonstrated that there exist two quaternary structures (deoxy and oxy) for the tetramer and two tertiary structures for each individual chain (liganded and unliganded). Based on the structural results and other data, Perutz (2, 3) proposed a stereochemical mechanism for cooperativity, in which salt bridges (some with ionizable protons in the neutral pH range) provide the link between ligand-induced tertiary structural changes and the relative stability of the two quaternary forms. To examine the thermodynamic correlates of the Perutz mechanism, its elements were incorporated into a statistical-mechanical model (4) (referred to as SK in what follows) that utilizes a partition function describing the influence of homotropic (oxygen) and heterotropic (protons and 2,3-bisphosphoglycerate) effectors on the set of contributing structures. It was found that the model was able to provide a satisfactory description of the cooperativity in ligand binding, the alkaline Bohr effect, the effect of 2,3-bisphosphoglycerate on ligand affinity, and the influence of chemical modifications and certain mutations on these properties (4-6). Further, the values of the model parameters, which correspond to physically meaningful quantities, were in the range suggested by independent estimates, thus providing support for the basic postulates of the Perutz mechanism.The structural, spectroscopic, and thermodynamic data on hemoglobin that have become available since the model was proposed call for its reevaluation at this time. Of particular importance are the structural results concerning the nature of tertiary-quaternary coupling. It is now clear from comparisons of crystal structures of unliganded d...

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Haemoglobin: Cooperativity in Protein–Ligand Interactions

Yuan

2010

Encyclopedia of Life Sciences

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Haemoglobin (Hb) is an essential component of the circulatory system of vertebrates. Its chief physiological function is to transport oxygen from the lungs to the tissues. Hb binds oxygen cooperatively, that is the affinity of the protein for the first oxygen molecule is less than that for subsequent oxygen molecules. Human adult Hb was among the first proteins whose complete three‐dimensional structure was determined by X‐ray crystallography and it has been used as a model for understanding allosteric proteins. Recent X‐ray crystallographic and multinuclear NMR (nuclear magnetic resonance) studies of both ligated and unligated forms of Hb have shown that many structures exist in crystalline and solution states. These results have challenged the classical two‐structure allosteric model of this protein. To understand Hb at the atomic level, we need to correlate the structural, dynamic and functional properties of hemoglobin in solution. Key Concepts: There are many T‐ and R‐types of crystal structures of unligated and ligated forms of haemoglobin, in contrast to the classical two‐structure model for haemoglobin allostery. The structures of haemoglobin in both unligated and ligated forms in solution are different from those in crystals and exist as dynamic ensembles of various structures. The ligand‐binding data for proximal histidyl‐detached recombinant haemoglobins show that Perutz's proximal histidyl coupling mechanism contributes approximately two‐thirds to the total interaction energy between haems and that there are alternative coupling pathways for the remaining third. The Bohr effect, a heterotropic effect, is an excellent example of a global network of electrostatic interactions, rather than a few specific amino acid residues, that play a dominant role in an important physiological function of haemoglobin. Recent experimental results strongly suggest that allosteric proteins, such as haemoglobin, may require multiple pathways for signal communication, as is illustrated in the cooperative oxygenation and in the Bohr effect. Haemoglobin is a molecule with considerable plasticity. The classical two‐structure mechanism for haemoglobin allostery cannot account for the structure, dynamics and function of the haemoglobin molecule and needs revision.

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Proton nuclear magnetic resonance investigation of structural changes associated with cooperative oxygenation of human adult hemoglobin

Cited by 76 publications

References 19 publications

A quantitative model for the cooperative mechanism of human hemoglobin.

A quantitative model for the cooperative mechanism of human hemoglobin.

Structure-specific model of hemoglobin cooperativity.

Haemoglobin: Cooperativity in Protein–Ligand Interactions

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