Deer mouse hemoglobin exhibits a lowered oxygen affinity owing to mobility of the E helix

Inoguchi, Noriko; Oshlo, Jake R.; Natarajan, Chandrasekhar; Weber, Roy E.; Fago, Angela; Storz, Jay F.; Moriyama, Hideaki

doi:10.1107/s1744309113005708

Cited by 8 publications

(18 citation statements)

References 38 publications

(36 reference statements)

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“…This observation suggests that – as in bovine Hb (Weber et al 2014) – the T-R shift of deer mouse Hb upon oxygenation is considerably endothermic in nature, whereas the endothermic dissociation of ionic cofactors upon oxygenation plays a minor role. This endothermic transition in quaternary structure correlates with a tighter α1β2 sliding subunit interface identified in crystallographic studies of deer mouse recombinant Hb (Inoguchi et al 2013), with additional interactions between αArg92 and βGln39 and between αArg92 and βAsp43, which are both lacking in human HbA. However, the molecular mechanisms underlying why DPG markedly affects O 2 affinity but not the enthalpy of oxygenation remains to be clarified.…”

Section: Discussionmentioning

confidence: 79%

Bohr effect and temperature sensitivity of hemoglobins from highland and lowland deer mice

Jensen¹,

Storz²,

Fago³

2016

Comparative Biochemistry and Physiology Part A: Molecular &

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An important means of physiological adaptation to environmental hypoxia is an increased oxygen (O2) affinity of the hemoglobin (Hb) that can help secure high O2 saturation of arterial blood. However, the trade-off associated with a high Hb-O2 affinity is that it can compromise O2 unloading in the systemic capillaries. High-altitude deer mice (Peromyscus maniculatus) have evolved an increased Hb-O2 affinity relative to lowland conspecifics, but it is not known whether they have also evolved compensatory mechanisms to facilitate O2 unloading to respiring tissues. Here we investigate the effects of pH (Bohr effect) and temperature on the O2-affinity of high- and low-altitude deer mouse Hb variants, as these properties can potentially facilitate O2 unloading to metabolizing tissues. Our experiments revealed that Bohr factors for the high- and low-altitude Hb variants are very similar in spite of the differences in O2-affinity. The Bohr factors of deer mouse Hbs are also comparable to those of other mammalian Hbs. In contrast, the high- and low-altitude variants of deer mouse Hb exhibited similarly low temperature sensitivities that were independent of red blood cell anionic cofactors, suggesting an appreciable endothermic allosteric transition upon oxygenation. In conclusion, high-altitude deer mice have evolved an adaptive increase in Hb-O2 affinity, but this is not associated with compensatory changes in sensitivity to changes in pH or temperature. Instead, it appears that the elevated Hb-O2 affinity in high-altitude deer mice is compensated by an associated increase in the tissue diffusion capacity of O2 (via increased muscle capillarization), which promotes O2 unloading.

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Section: Discussionmentioning

confidence: 79%

Bohr effect and temperature sensitivity of hemoglobins from highland and lowland deer mice

Jensen¹,

Storz²,

Fago³

2016

Comparative Biochemistry and Physiology Part A: Molecular &

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“…Recombinant highland deer mouse hemoglobin in the carbon monoxide format was produced as previously described [20, 22]. Purified highland hemoglobin was crystalized with the vapor diffusion method using 26% (w/v) PEG 3350 in 50 mM sodium/potassium phosphate buffer, pH 8.0, at 299 K in the airtight vial purged with carbon monoxide (S1 Fig).…”

Section: Methodsmentioning

confidence: 99%

“…The lowland hemoglobin variant was crystalized under the same conditions as the highland variant with the exception that 28% (w/v) PEG 3350 was used; however, the same fibrous format was not observed. Crystals of lowland hemoglobin were produced only with 14 mM calcium chloride without glutathione and 2,4-pentanediol [20]. …”

Section: Methodsmentioning

confidence: 99%

“…Previously, we solved the 3D structure of the lowland hemoglobin variant of deer mice (PDB ID: 4H2L), and structural comparisons with human hemoglobin showed that αHis45 is oriented toward the solvent in this lowland variant, whereas αHis45 in human hemoglobin interacts with heme [20]. This unique αHis45 configuration was also observed in horse hemoglobin crystallized with 2-[4-(3,5-dichlorophenylureido) phenoxy]-2-methylpropionic acid (L35) (PDB ID: 2D5X) [21].…”

Section: Introductionmentioning

confidence: 99%

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Alteration of the α1β2/α2β1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice

Inoguchi¹,

Mizuno²,

Baba³

et al. 2017

PLoS ONE

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BackgroundDeer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant.ResultsHighland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 Å. Using the smaller unit cell crystal, the structure was solved at 2.2 Å resolution. The asymmetric unit contained two tetrameric hemoglobin molecules.ConclusionsThe analyses revealed that αPro50 in the highland hemoglobin variant promoted a stable interaction between αHis45 and heme that was not seen in the αHis50 lowland variant. The αPro50 mutation also altered the nature of atomic contacts at the α1β2/α2β1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites.

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“…In the article by Inoguchi et al (2013) the affiliation for two of the authors, Angela Fago and Roy E. Weber, was given incorrectly. The correct affiliation is Zoophysiology, Department of Bioscience, Aarhus University, Aarhus, Denmark.…”

Section: Structural Biology and Crystallization Communicationsmentioning

confidence: 99%