Hemoglobin tertiary structural change on ligand binding its role in the co-operative mechanism

Gelin, Bruce R.; Lee, Angel Wai-mun; Karplus, Martin

doi:10.1016/0022-2836(83)90042-6

Cited by 170 publications

(103 citation statements)

References 69 publications

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“…The new model introduced ligand-binding restraints coupled to both tertiary and quaternary structural change. This is in accord with the more detailed description based on empirical energy function calculations (Gelin et al 1983), which have demonstrated that the low affinity of the deoxy quaternary structure arises not only from the perturbation of salt bridges but also from steric constraints imposed by contacts at the a 1 b 2 and a 2 b 1 interfaces that transmit the ligation-induced strain in the ''allosteric core'' (the heme, proximal histidine, F helix, and the FG corner of each subunit) from one subunit to another.…”

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confidence: 85%

Allostery and cooperativity revisited

2008

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Although phenomenlogical models that account for cooperativity in allosteric systems date back to the early and mid-60's (e.g., the KNF and MWC models), there is resurgent interest in the topic due to the recent experimental and computational studies that attempted to reveal, at an atomistic level, how allostery actually works. In this review, using systems for which atomistic simulations have been carried out in our groups as examples, we describe the current understanding of allostery, how the mechanisms go beyond the classical MWC/Pauling-KNF descriptions, and point out that the ''new view'' of allostery, emphasizing ''population shifts,'' is, in fact, an ''old view.'' The presentation offers not only an up-to-date description of allostery from a theoretical/computational perspective, but also helps to resolve several outstanding issues concerning allostery.

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confidence: 85%

Allostery and cooperativity revisited

2008

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“…These results further suggest that the Perutz salt bridges are not the sole source of the low oxygen affinity of T, as suggested earlier (48,54,55). It appears that understanding the structural basis of oxygen affinity in hemoglobin still remains a major unsolved problem (45).…”

Section: Mwc T R T Rsupporting

confidence: 82%

Experimental basis for a new allosteric model for multisubunit proteins

Viappiani

Abbruzzetti

Ronda³

et al. 2014

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

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Monod, Wyman, and Changeux (MWC) explained allostery in multisubunit proteins with a widely applied theoretical model in which binding of small molecules, so-called allosteric effectors, affects reactivity by altering the equilibrium between more reactive (R) and less reactive (T) quaternary structures. In their model, each quaternary structure has a single reactivity. Here, we use silica gels to trap protein conformations and a new kind of laser photolysis experiment to show that hemoglobin, the paradigm of allostery, exhibits two ligand binding phases with the same fast and slow rates in both R and T quaternary structures. Allosteric effectors change the fraction of each phase but not the rates. These surprising results are readily explained by the simplest possible extension of the MWC model to include a preequilibrium between two tertiary conformations that have the same functional properties within each quaternary structure. They also have important implications for the long-standing question of a structural explanation for the difference in hemoglobin oxygen affinity of the two quaternary structures.S mall molecules can regulate protein reactivity by binding to residues distant from the active site, a phenomenon known as allostery. The classic theoretical model proposed by Monod, Wyman, and Changeux (MWC) (1, 2) for explaining this phenomenon considered only proteins with multiple subunits, and the two-state allosteric model of MWC was originally used by them to explain the functional properties of the hemoglobin tetramer, the "honorary enzyme" (1, 3). This famous model has since been applied to a wide variety of other systems in biology, including ligand-gated ion channels, G-protein-coupled receptors, nuclear receptors, and supramolecular assemblies such as chaperonins (4-7). In the case of hemoglobin, the paradigm of allostery, MWC makes two key postulates that have been extensively tested by experiments. Oxygen binding to the deoxy quaternary structure (T) is noncooperative; cooperativity arises from a shift in the population from the low-affinity T quaternary structure to the high-affinity R quaternary structure as the oxygen concentration is increased. The second postulate is that allosteric effectors regulate oxygen affinity by altering only the R ⇄ T preequilibrium. Investigations of hemoglobin focused primarily on the first postulate, which was finally confirmed by single-crystal oxygen-binding measurements that ruled out a sequential model (8) and ended a 25-y controversy (9-12). The second is of more general interest because it applies to all multisubunit proteins exhibiting allosteric behavior and has been known for many years to be inconsistent with the fact that allosteric effectors markedly affect oxygen affinity without changing the quaternary preequilibrium [see data summaries by Imai, Yonetani, and coworkers (13,14)]. The change in oxygen affinity constants, K T and K R , with conditions was interpreted as indicating that tertiary conformations must be affected or that more than two quat...

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“…Binding of oxygen to the heme groups results in destabilization of these salt bridges by a steric mechanism involving undoming of the hemes, as Perutz suggested in his model for cooperative oxygen binding (15) (for a recent review, see ref. 9) and was confirmed by atomic-level energy calculations, which introduced the concept of an allosteric core (16).…”

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confidence: 73%

“…5B). Perutz had identified a set of salt bridges as being important for stabilizing the T state (15), although there are additional contributions to stabilizing the T state versus the R state (10,16). Six of the salt bridges are at the interfaces between subunits and two are internal to the β-subunits.…”

Section: Resultsmentioning

confidence: 99%

Unsuspected pathway of the allosteric transition in hemoglobin

Fischer

Olsen

Nam

et al. 2011

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

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Large conformational transitions play an essential role in the function of many proteins, but experiments do not provide the atomic details of the path followed in going from one end structure to the other. For the hemoglobin tetramer, the transition path between the unliganded (T) and tetraoxygenated (R) structures is not known, which limits our understanding of the cooperative mechanism in this classic allosteric system, where both tertiary and quaternary changes are involved. The conjugate peak refinement algorithm is used to compute an unbiased minimum energy path at atomic detail between the two end states. Although the results confirm some of the proposals of Perutz [Perutz MF (1970) Stereochemistry of cooperative effects in haemoglobin. Nature 228:726-734], the subunit motions do not follow the textbook description of a simple rotation of one αβ-dimer relative to the other. Instead, the path consists of two sequential quaternary rotations, each involving different subdomains and axes. The quaternary transitions are preceded and followed by phases of tertiary structural changes. The results explain the recent photodissociation measurements, which suggest that the quaternary transition has a fast (2 μs) as well as a slow (20 μs) component and provide a testable model for single molecule FRET experiments.conformational change | cooperativity | domain motion | protein hinges M any proteins undergo large conformational transitions that are essential for their functions (1-3). The transitions can occur in monomers such as the myosin molecular motor (4-6), in multisubunit complexes such as the chaperone GroEL (7), and in systems such as the flagellar motor of bacteria, which is composed of several hundred proteins (8). Probably the most studied example is the T (tense) to R (relaxed) transition in the vertebrate hemoglobin tetramer (Hb) (9-11), for which the conformational transition increases the efficiency of oxygen transport. Hemoglobin, which is composed of two identical α-and two identical β-subunits, is the paradigm for the development of models of cooperativity and allosteric regulation in proteins (9-13). Phenomenologically, the positive cooperativity involves the increase in the affinity for oxygen of unliganded subunits upon the successive binding of oxygen to other subunits. This is achieved by structural changes within subunits (tertiary changes) and between subunits (quaternary changes). Based on the superposition of the crystallographic structures for the deoxy unliganded T state and the fully liganded R state of the protein, the quaternary T → R transition has been described as involving primarily an approximately 15°rotation of one "dimer" (α 1 β 1 ) relative to the other (α 2 β 2 ) around a virtual axis (Fig. 1A) (9, 14). Together with a small relative translation of the αβ-dimers, this reduces the central cavity between the dimers (a channel along the C2 axis of symmetry), where the heterotropic effector 2,3-bisphosphoglycerate is bound in the T state. An important aspect of these structural ch...

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Hemoglobin tertiary structural change on ligand binding its role in the co-operative mechanism

Cited by 170 publications

References 69 publications

Allostery and cooperativity revisited

Allostery and cooperativity revisited

Experimental basis for a new allosteric model for multisubunit proteins

Unsuspected pathway of the allosteric transition in hemoglobin

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