A new mode for heme-heme interactions in hemoglobin associated with distal perturbations

Levy, Allan H.; Sharma, Vandna; Zhang, Lu; Rifkind, Joseph M.

doi:10.1016/s0006-3495(92)81879-9

Cited by 32 publications

(31 citation statements)

References 33 publications

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“…Still, elements of the two-state model, which permits global quaternary rearrangement, but no sequential inter-subunit coupling, have frequently been questioned from a wide range of perspectives (9)(10)(11)(12)(13)(14)(15)(16). Systematic deviations from the two-state model become most apparent when the Hb system is resolved into its separate, partially ligated microstates, some of which are asymmetrically ligated (17)(18)(19)(20)(21). The fact remains that experimental perturbations to the Hb system, when limited to symmetric modifications (solvent conditions, allosteric effectors, globin modifications), cannot, even in principle, yield a clear distinction between a single quaternary (cross-dimer) effect vs. two tertiary (intradimer) effects.…”

mentioning

confidence: 99%

Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

Ackers

Dalessio

Lew

et al. 2002

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

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The mechanism of cooperativity in the human hemoglobin tetramer (a dimer of ␣␤ dimers) has historically been modeled as a simple two-state system in which a low-affinity structural form (T) switches, on ligation, to a high-affinity form (R), yielding a net loss of hydrogen bonds and salt bridges in the dimer-dimer interface. Modifications that weaken these cross-dimer contacts destabilize the quaternary T tetramer, leading to decreased cooperativity and enhanced ligand affinity, as demonstrated in many studies on symmetric double modifications, i.e., a residue site modified in both ␣-or both ␤-subunits. In this work, hybrid tetramers have been prepared with only one modified residue, yielding molecules composed of a wild-type dimer and a modified dimer. It is observed that the cooperative free energy of ligation to the modified dimer is perturbed to the same extent whether in the hybrid tetramer or in the doubly modified tetramer. The cooperative free energy of ligation to the wild-type dimer is unperturbed, even in the hybrid tetramer, and despite the overall destabilization of the T tetramer by the modification. This asymmetric response by the two dimers within the same tetramer shows that loss of dimer-dimer contacts is not communicated across the dimer-dimer interface, but is transmitted through the dimer that bears the modified residue. These observations are interpreted in terms of a previously proposed dimer-based model of cooperativity with an additional quaternary (T͞R) component.M any tertiary and quaternary conformational events important for catalysis and cooperativity in biological macromolecules are energetically unfavorable, and must be driven by favorable free energy of ligand binding. In the case of human hemoglobin (Hb), initial binding of O 2 to the heme Fe drives intrinsically unfavorable conformation change within the globin. The associated energetic ''penalty'' results in lower binding constants for initial ligation. However, penalties for the additional binding steps are progressively reduced, generating Hb's characteristic sigmoidal binding curve. Contributing to this curve are the partially ligated Hb intermediates, composed of two different subunit types (␣ and ␤) with four binding sites (␣ 1 , ␤ 1 , ␣ 2 , ␤ 2 ). Up to four labile ligands (O 2 ) are present on each tetramer in multiple configurations of site occupancy within at least two distinct quaternary structures (T and R). The challenge in understanding the mechanism of Hb cooperativity has been to identify and measure the separate energetic penalties for each O 2 binding step, and then to correlate individual penalties with specific structural events.To approach a resolution of this complex problem, energetic components of the system's ligation intermediates were evaluated with no prior assumptions as to their quaternary structures. Analysis of the thermodynamic linkages between dimertetramer assembly and O 2 binding permitted the ligand binding constant of the noncooperative free dimer to be used as the thermodynamic reference s...

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mentioning

confidence: 99%

Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

Ackers

Dalessio

Lew

et al. 2002

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

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“…The role of H 2 O 2 in E-selectin expression was examined further in the lungs of mice (Hb mut ) expressing an Hb mutation that causes Hb instability and decreased oxygen affinity to Hb (24,25), thereby increasing hypoxia-induced Hb autoxidation and H 2 O 2 production (16,17). Our previous findings indicate that in lungs of Hb mut mice, hypoxia increases erythrocyteendothelial H 2 O 2 transfer as well as Ca 21 -dependent endothelial P-selectin expression (20).…”

Section: Hypoxia Causes Erythrocyte-derived H 2 O 2 Proinflammatory Ementioning

confidence: 99%

“…Here, we consider the release of H 2 O 2 from erythrocytes as a possible mechanism. In hypoxic erythrocytes, the partial deoxygenation of hemoglobin (Hb) dramatically increases the rate of autoxidation in the oxygenated domains of Hb, resulting in the formation of superoxide and H 2 O 2 (16,17). A fraction of the deoxy-Hb binds the erythrocyte membrane protein, band 3 (18, 19).…”

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confidence: 99%

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

Huertas

Das²,

Emin³

et al. 2013

Am J Respir Cell Mol Biol

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Although exposure to ambient hypoxia is known to cause proinflammatory vascular responses, the mechanisms initiating these responses are not understood. We tested the hypothesis that in systemic hypoxia, erythrocyte-derived H 2 O 2 induces proinflammatory gene transcription in vascular endothelium. We exposed mice or isolated, perfused murine lungs to 4 hours of hypoxia (8% O 2 ). Leukocyte counts increased in the bronchoalveolar lavage. The expression of leukocyte adhesion receptors, reactive oxygen species, and protein tyrosine phosphorylation increased in freshly recovered lung endothelial cells (FLECs). These effects were inhibited by extracellular catalase and by the removal of erythrocytes, indicating that the responses were attributable to erythrocyte-derived H 2 O 2 . Concomitant nuclear translocation of the p65 subunit of NF-kB and hypoxiainducible factor-1a stabilization in FLECs occurred only in the presence of erythrocytes. Hemoglobin binding to the erythrocyte membrane protein, band 3, induced the release of H 2 O 2 from erythrocytes and the p65 translocation in FLECs. These data indicate for the first time, to our knowledge, that erythrocytes are responsible for endothelial transcriptional responses in hypoxia.Keywords: hypoxia; erythrocytes; endothelium; lung; inflammation Systemic hypoxia, which is characterized by a decrease in the partial pressure of oxygen in blood (PO 2 ), results from a lack of oxygen in inhaled breath, or from impaired blood oxygenation because of lung disease. The circulatory response to a decrease of PO 2 is best characterized by pulmonary arterial vasoconstriction, a protective strategy that redistributes the pulmonary blood flow from hypoxic to well-ventilated regions of the lung. An additional vascular effect may involve a hypoxia-induced innate immune response, characterized by leukocyte activation and tissue injury (1). However, this effect remains controversial. Support for the immune effect derives from evidence in animal models that ambient hypoxia causes lung injury (2-5), systemic inflammation (4, 5), and vascular leakage (2, 6). A 4-hour exposure to 8% O 2 in mice activates NF-kB in astrocytes and hepatocytes (7), suggesting that hypoxia-induced proinflammatory gene transcription occurs in these cells.The evidence opposing the hypoxic immune response comes from lung lymph flow studies in adult sheep. According to these studies, ambient hypoxia does not increase lung microvascular permeability to proteins, and it does not cause pulmonary edema (8, 9). The clinical evidence for the hypoxic immune effect is mixed, and is based on studies of high-altitude pulmonary edema (HAPE), a form of lung injury that follows exposure to hypoxia at high altitude. Radioactive tracer studies in patients with HAPE confirm the sheep data insofar as lung microvascular permeability does not increase (10). Several studies indicate that the bronchoalveolar lavage (BAL) of patients with HAPE is enriched in leukocytes, proteins, and proinflammatory factors, indicating that HAPE causes lu...

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“…The configuration of the residues lining the distal side of the heme pocket (where O 2 binds and where geographical alteration can be made by oxygenation) is thought to play a part in controlling access of the ligand to the heme pocket. Nevertheless, the possibility of subunit interactions originating from or being transmitted via distal effects has (for the most part) been neglected [29]. Relatively little attention has been paid to the autoxidation of HbO 2 (oxidation of ferrous heme iron by bound O 2 ), even though autoxidation is inevitable in nature for all O 2 -binding heme proteins.…”

Section: The Mean ± Standard Deviation Of Transit Time Of Blood Samplmentioning

confidence: 99%

“…This has been coupled with a tendency for structural analyses to focus on the changes at the proximal side of the heme and at the α 1 -β 2 (and α 2 -β 1 ) interface, as mentioned above. This is despite the fact that the configuration of the residues lining the distal side of the heme pocket (where molecular O 2 binds) are also altered by oxygenation, and are thought to have a role in controlling access of the ligand to the heme pocket [29]. Hence, the possibility of subunit interactions originating from or being transmitted via distal side effects has, for the most part, been neglected.…”

Section: Introductionmentioning

confidence: 99%

New Mode (Molecular-Sensing) of Heinz Body Formation Mechanisms Inherent in Human Erythrocytes: Basis for Understanding of Clinical Aspects of Drug-Induced Hemolytic Anemia and the Like

Sugawara¹

2013

J Bioanal Biomed

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The human hemoglobin (Hb) molecule (α 2 β 2 ) has two types of α-β interface (i.e., α 1 -β 1 [and α 2 -β 2 ] and α 1 -β 2 [and α 2 -β 1 ]). The latter α 1 -β 2 (and α 2 -β 1 ) interface is associated with cooperative O 2 binding, and exhibits principal roles if the molecule goes from its deoxygenated to oxygenated quaternary structure. The role of the former α 1 -β 1 (and α 2 -β 2 ) interface has been unclear for a long time. In this regard, important and intriguing observations have been accumulating, so that a new gaze can be focused on the α 1 -β 1 (and α 2 -β 2 ) interface. Our most recent findings suggest that the α 1 -β 1 (and α 2 -β 2 ) interface may exert delicate control of the intrinsic tilting capability of the distal (E7) His residues (i.e., α58His (E7) in the α chain and β63His (E7) in the β chain) depending on internal and external conditions of the erythrocyte to lead to degradation of Hb to hemichrome, and subsequent clustering of Heinz bodies within the erythrocyte. In the spleen, rigid intra-erythrocytic hemichrome inclusions (Heinz bodies) act as "sticking points", so Heinz body-containing red cells become trapped and undergo hemolysis. In this article, we first provide our necessary basic experimental findings that led us to grasp molecular biosensing mechanisms inherent in human erythrocytes for the appreciation of aging and determination of their lifespan, and summarize their roles in physiology. We then discuss how these accomplishments contribute to deeper understanding of clinical aspects of drug-induced hemolytic anemia, defects in the intra-erythrocytic reducing system and unstable Hb disease, in which the mechanisms for acute hemolytic crisis cannot be explained on the basis of conventional views.

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A new mode for heme-heme interactions in hemoglobin associated with distal perturbations

Cited by 32 publications

References 33 publications

Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

Erythrocytes Induce Proinflammatory Endothelial Activation in Hypoxia

New Mode (Molecular-Sensing) of Heinz Body Formation Mechanisms Inherent in Human Erythrocytes: Basis for Understanding of Clinical Aspects of Drug-Induced Hemolytic Anemia and the Like

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