Molecular models for the putative dimer of sea lamprey hemoglobin.

Abstract

The known structures for the tetramers of mammalian and clam hemoglobins provide a point of departure for the modeling of putative dimers of lamprey hemoglobin. The association of subunits is dissimilar for the clam and mammalian tetramers; the superposition of the molecular model for lamprey methemoglobin onto the mammalian and clam tetramers gives five distinct dimers. After energy minimization of the interface regions of the five models, three models afford promising interactions between side chains. One model is analogous to the al.f2 pairing of subunits of mammalian hemoglobins. The other two models are similar to the interfaces between the E and F helices and between the A and B helices of clam hemoglobin. Although the model based on the alf2 mode of association provides the best explanation of biochemical properties of lamprey hemoglobin, such as the Bohr effect and the dependency of dimer formation on pH, interfaces between the E and F and the A and B helices could be important in the aggregation of monomers of lamprey hemoglobin beyond the level of the dimer.Cooperative phenomena of vertebrate hemoglobins evolved some 500 million years ago over a relatively brief span of 25-50 million years. On the basis of work by Goodman et al.(1), the ancestral globin of the sea lamprey represents the earliest stage in the evolution of the present day tetramer. As fossil records reveal little change in the morphology ofthe sea lamprey (2), the properties of the hemoglobin of modem-day sea lamprey (Petromyzon marinus) may be representative of those of the ancestral globin. The globins of sea lamprey are primarily monomeric. However, as the pH falls below 7.0, hemoglobins of the lamprey aggregate (3). The precise nature of the aggregated state(s) of lamprey hemoglobin is unclear, although much evidence exists for at least a dimer. Thermodynamically coupled to the aggregation phenomenon is the uptake of protons and the release of oxygen. Monomeric lamprey hemoglobin has a greater affinity for oxygen than do the aggregates. Thus, as lamprey hemoglobin accepts oxygen, the monomer-oligomer equilibrium shifts in favor of the monomer. Further, the transition from oligomer to monomer releases protons, a phenomenon analogous to the Bohr effect of mammalian hemoglobins.The superposition of monomers of lamprey hemoglobin onto the subunits of the mammalian and clam (Scapharca inaequivalvis) tetramers provides five distinct models of the putative dimer of lamprey hemoglobin. Only the models analogous to the a1/32 interface of the mammalian tetramer and to the E-F and A-B interfaces of the clam tetramer are possible for lamprey hemoglobin. The lamprey "a1/32" interface not only bears close resemblance to its mammalian counterpart, consistent with the notion that lamprey hemoglobin is an evolutionary precursor of the cooperative tetramer, but also provides explanations for the Bohr effect, the dependence of aggregation on pH, and the cooperative interactions during the uptake of oxygen by the dimer. However, either the E-F o...

Crystal Structures of Deoxy- and Carbonmonoxyhemoglobin F1 from the Hagfish Eptatretus burgeri

“…The low metabolic rate of hagfish does not seem to require a highly cooperative oxygen carrier, and our structures confirm that F1 is unable to form monomer-monomer interactions of the kind found in higher vertebrate Hbs. The long N-terminal extension and the deletion between the G and H helices make both ␣ 1 ␤ 1 -and ␣ 1 ␤ 2 -type interactions impossible (4). It has been suggested that hagfish Hbs represent an intermediate between invertebrate and vertebrate Hbs (47), but we see no evidence of direct heme-heme interaction as found in the Hb of the clam S. inaequivalvis (27).…”

“…In the case of lamprey Hbs, the dissociation of ligands promotes oligomerization of the protein. On the basis of a monomer structure of the cyanidebound ferric form, Honzatko and Hendrickson (4) suggested that the subunit interfaces of the deoxy-Hb oligomer were the same as the ␣ 1 ␤ 2 interface of the ␣ 2 ␤ 2 tetramer. Recently, however, Heaslet and Royer (5) solved the x-ray structure of lamprey deoxy-Hb and found a dimer with an interface between the E helix and AB corner, totally different from any of the interfaces in the ␣ 2 ␤ 2 tetramer.…”

Gene cooption and convergent evolution of oxygen transport hemoglobins in jawed and jawless vertebrates

“…The formation of heteromultimers composed of unlike subunits appears superficially similar to the α 2 β 2 heterotetramers of most gnathostomes, but the oxygenation-linked transition in quaternary structure is completely different. The intersubunit contacts of heterotetrameric gnathostome Hbs primarily involve the C, G, and H helices of the globin chain subunits (51), whereas the contact surfaces of the deoxygenated, homodimeric cyclostome Hbs involve the E helix and the AB corner, such that the heme groups are in almost direct contact (52)(53)(54)(55). The heme-heme interactions of cyclostome Hbs are intriguingly similar to those of the homodimer of Cygb (23,38,39,56,57), an observation that makes sense in light of our inferred phylogenetic relationship between these two globin proteins (Fig.…”

The 2.7 Å crystal structure of deoxygenated hemoglobin from the sea lamprey (Petromyzon marinus): structural basis for a lowered oxygen affinity and Bohr effect

“…On the basis of sequence analysis, Li and Riggs proposed that the dimer would form an interface similar to the α 1 β 2 interface of human hemoglobin [13]. Additionally, Honzatko and Hendrickson have proposed three possible dimer assemblages based on those observed in human and Scapharca (mollusc) hemoglobins [14].…”