Novel Mechanisms of pH Sensitivity in Tuna Hemoglobin

Yokoyama, Takeshi; Chong, Khoon Tee; Miyazaki, Gentaro; Morimoto, Hideki; Shih, Daniel Tzu-Bi; Unzai, Satoru; Tame, J.R.H.; Park, Sam-Yong

doi:10.1074/jbc.m401740200

Cited by 70 publications

(40 citation statements)

References 55 publications

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“…Thus, in going from the R to the T state the relative shift at the switch region of the ␣ 1 ␤ 2 (␣ 2 ␤ 1 ) interface remains essentially the same in HbTb and Hb1Tn with respect to HbA. The superposition parameters in Antarctic fish Hbs are also similar to those displayed by trout and tuna Hbs (6,25). The small differences with respect to HbA may be correlated to the acetylation of the N-terminal residues in the ␣ chains (11), a structural feature common to all teleost Hbs.…”

Section: Resultssupporting

confidence: 59%

“…Specific interactions, typical of the HbA T state, are maintained in the present structure and include the salt bridge between Lys40␣ (C5) and the carboxyl group of C-terminal His146␤ (HC3), the hydrogen bond between the charged chain of Arg142␣ (HC3) and the backbone oxygen atom of Val34␤ (B16) and the hydrogen bonds between the side chain of Asp99␤ (G1) and those of Tyr42␣ (C6)and Asn98␣ (G4). Unexpectedly, the tetramer is also stabilized by the hydrogen-bonding interactions between aspartic side chains, that are usually associated to the T state of Root-effect Hbs (6,19,21). Indeed, the omit map clearly reveals the spatial proximity of the side chains of Asp95␣ (G1), Asp99␤ (G1), and Asp101␤(G3) at both the ␣ 1 ␤ 2 and ␣ 2 ␤ 1 interfaces (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The Root effect has been functionally related to the filling of the fish swim bladder with gas and to the supply of oxygen to the typically un-capillarized fish retina (3). Although the physiology and the structural basis of the Root effect have been addressed in a large number of studies (2)(3)(4)(5)(6)(7)(8), it remains a mystery in many aspects. Over the years, several hypotheses on the structural determinants of the Root effect have been suggested.…”

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confidence: 99%

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An Order-Disorder Transition Plays a Role in Switching Off the Root Effect in Fish Hemoglobins

Vergara

Vitagliano

Merlino

et al. 2010

Journal of Biological Chemistry

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The Root effect is a widespread property among fish hemoglobins whose structural basis remains largely obscure. Here we report a crystallographic and spectroscopic characterization of the non-Root-effect hemoglobin isolated from the Antarctic fish Trematomus newnesi in the deoxygenated form. The crystal structure unveils that the T state of this hemoglobin is stabilized by a strong H-bond between the side chains of Asp95␣ and Asp101␤ at the ␣ 1 ␤ 2 and ␣ 2 ␤ 1 interfaces. This unexpected finding undermines the accepted paradigm that correlates the presence of this unusual H-bond with the occurrence of the Root effect. Surprisingly, the T state is characterized by an atypical flexibility of two ␣ chains within the tetramer. Indeed, regions such as the CD␣ corner and the EF␣ pocket, which are normally well ordered in the T state of tetrameric hemoglobins, display high B-factors and non-continuous electron densities. This flexibility also leads to unusual distances between the heme iron and the proximal and distal His residues. These observations are in line with Raman micro-spectroscopy studies carried out both in solution and in the crystal state. The findings here presented suggest that in fish hemoglobins the Root effect may be switched off through a significant destabilization of the T state regardless of the presence of the inter-aspartic H-bond. Similar mechanisms may also operate for other non-Root effect hemoglobins. The implications of the flexibility of the CD␣ corner for the mechanism of the T-R transition in tetrameric hemoglobins are also discussed.Protein crystallography is a fundamental tool to interpret protein function at atomic level. Although this approach is usually effective in understanding the general trends of biological processes, it is often difficult to single out the structural details important for their fine regulation. The case of hemoglobin (Hb) 2 is emblematic in this context. Since the pioneering studies by Perutz, the basic features of Hb function (identification of distinct quaternary states, transitions between these states, etc.) have been elucidated at atomic level. However, the identification of the structural features at the basis of the different properties of Hbs, isolated from organisms living under different conditions, has proven to be highly elusive. In this framework, the so-called Root effect represents one of the most puzzling issues.The Root effect, first described in 1931, is a peculiar property of some fish Hbs that is associated with an extremely low affinity for oxygen at low pH values (1, 2). Notably, at oxygen partial pressures adequate to saturate most of vertebrate Hbs, Rooteffect Hbs generally remain in a deoxygenated state at acidic pH values. The Root effect has been functionally related to the filling of the fish swim bladder with gas and to the supply of oxygen to the typically un-capillarized fish retina (3). Although the physiology and the structural basis of the Root effect have been addressed in a large number of studies (2-8), it remains a myst...

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Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

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An Order-Disorder Transition Plays a Role in Switching Off the Root Effect in Fish Hemoglobins

Vergara

Vitagliano

Merlino

et al. 2010

Journal of Biological Chemistry

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“…8 In this scenario, it is worth noting that structural characterization of AF-Hbs in liganded or deoxygenated states 9-14 have played a major role in the development of the current hypotheses on the structural bases of the Root effect. 6,7,11,13,15 Studies on AF-Hbs have also demonstrated that they undergo a peculiar oxidation process. 14,[16][17][18] In contrast with mammalian Hbs, that essentially oxidize in their folded state to aquo/hydroxyl metHb forms, AF-Hbs oxidation leads to the formation of species such as bis-histidyl adducts [16][17][18] and pentacoordinated states 14,[17][18][19] that are typically associated with Hbs with lower structural complexity (monomeric and dimeric).…”

Section: Introductionmentioning

confidence: 97%

Combined crystallographic and spectroscopic analysis of Trematomus bernacchii hemoglobin highlights analogies and differences in the peculiar oxidation pathway of Antarctic fish hemoglobins

et al. 2009

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Recent studies have demonstrated that hemoglobins isolated from Antarctic fish undergo peculiar oxidation processes. Here we show, by combining crystallographic and spectroscopic data, that the oxidation pathway of Trematomus bernacchii hemoglobin (HbTb) is distinct from that observed for the major component of Trematomus newnesi (Hb1Tn), despite the high sequence identity of the two proteins and structural similarity of their ferrous and fully oxidized states. Resonance Raman analysis of HbTb autoxidation upon air-exposure reveals the absence of the oxidized pentacoordinated state that was observed for Hb1Tn. The HbTb oxidation pathway is characterized by two ferric species: an aquo hexacoordinated high spin state and a bis-histidyl hexacoordinated low spin form, which appear in the early stages of the oxidation process. The high resolution structure of an intermediate along the oxidation pathway has been determined at 1.4 A resolution. The analysis of the electron density of the heme pocket shows, for both the alpha and the beta iron, the coexistence of multiple binding states. In this partially oxidized form, HbTb exhibits significant deviations from the canonical R state both at the local and global level. The analysis of these modifications highlights the structural correlation between key functional regions of the protein.

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“…A similar program has been used recently to study the relaxation of scalar fields [21] as well as the photon production from a quark gluon plasma in thermal equilibrium [19].…”

Section: General Formulation: the Non-equilibrium Effective Actionmentioning

confidence: 99%

Particle abundance in a thermal plasma: Quantum kinetics versus Boltzmann equation

2005

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We study the abundance of a particle species in a thermalized plasma by introducing a quantum kinetic description based on the non-equilibrium effective action. A stochastic interpretation of quantum kinetics in terms of a Langevin equation emerges naturally. We consider a particle species that is stable in the vacuum and interacts with heavier particles that constitute a thermal bath in equilibrium. Asymptotic theory suggests a definition of a fully renormalized single particle distribution function. Its real time dynamics is completely determined by the non-equilibrium effective action which furnishes a Dyson-like resummation of the perturbative expansion. The distribution function reaches thermal equilibrium on a time scale ∼ 1/2 Γ k (T ) with Γ k (T ) being the quasiparticle relaxation rate. The equilibrium distribution function depends on the full spectral density as a consequence the fluctuation-dissipation relation. Such dependence leads to off-shell contributions to the particle abundance. A specific model of a bosonic field Φ in interaction with two heavier bosonic fields χ1,2 is studied. The decay of the heaviest particle and its recombination lead to a width of the spectral function for the particle Φ and to off-shell corrections to the abundance. We find substantial departures from the Bose-Einstein result both in the high temperature and the low temperature but high momentum region. In the latter the abundance is exponentially suppressed but larger than the Bose-Einstein result. We obtain the Boltzmann equation in renormalized perturbation theory and highlight the origin of the differences. Cosmological consequences are discussed: we argue that the corrections to the abundance of cold dark matter candidates are observationally negligible and that recombination erases any possible spectral distortions of the CMB. However we expect that the enhancement at high temperature may be important for baryogenesis.

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Novel Mechanisms of pH Sensitivity in Tuna Hemoglobin

Cited by 70 publications

References 55 publications

An Order-Disorder Transition Plays a Role in Switching Off the Root Effect in Fish Hemoglobins

An Order-Disorder Transition Plays a Role in Switching Off the Root Effect in Fish Hemoglobins

Combined crystallographic and spectroscopic analysis of Trematomus bernacchii hemoglobin highlights analogies and differences in the peculiar oxidation pathway of Antarctic fish hemoglobins

Particle abundance in a thermal plasma: Quantum kinetics versus Boltzmann equation

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