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

Abstract

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.

Acclimatization of low altitude-bred deer mice (Peromyscus maniculatus) to high altitude

“…Wild deer mice remain active throughout the year in the extreme HA habitat where they must overcome ambient hypoxia, cold temperatures, and food scarcity. They have evolved novel hemoglobin isoforms with increased O 2 binding affinity to surmount partially the low ambient O 2 availability (7,27,64); however, these isoforms are not always expressed and are insufficient to support the aerobic demands of deer mice fully, necessitating other strategies to increase O 2 uptake and delivery. Hammond et al (18) reported that deer mice that were raised and tested at LA exhibit higher aerobic capacity and basal metabolic rate than those that were either raised or acclimated as adults and tested at HA.…”

Crystal structure of hemoglobin from mouse (Mus musculus) compared with those from other small animals and humans

“…The heme groups of mouse met Hb and their environmental residues are shown as 2F o À F c electron-density maps in Fig. 4 (Inoguchi et al, 2013(Inoguchi et al, , 2017Pairet & Jaenicke, 2010;Shaanan, 1983;Vá squez et al, 1998;Fermi et al, 1984;Biswal & Vijayan, 2001). From the heme geometry, the distances between Fe and Geometry of the heme groups and their environment in mouse, human, DMouse and GPig Hbs.…”

Commentary: Hierarchical reductionism approach to understanding adaptive variation in animal performance

“…Molecular and genetic approaches have provided valuable insights into the biochemical mechanisms underlying this evolved change in Hb function. The specific amino acid replacements that are responsible for evolved changes in Hb-O2 affinity have been identified (Storz et al, 2012;Storz et al, 2010;Storz et al, 2009) and crystallographic studies have revealed the biophysical mechanisms by which mutations exert their effects (Inoguchi et al, 2017;Inoguchi et al, 2013;Natarajan et al, 2015). Protein engineering has shown that these modifications lead to increases in Hb-O2 affinity for isolated protein in vitro, without affecting the Bohr effect (Jensen et al, 2016;Natarajan et al, 2013).…”