Abstract
Hemoglobin from the leech Macrobdella decora belongs to the class of giant extracellular hexagonal bilayer globin structures found in annelid and vestimentiferan worms. These complexes consist of 144 heme-bearing subunits, exhibit a characteristic quaternary structure (2 x (6 x (3 x 4))), and contain tetramers as basic substructures that express cooperative oxygen binding and thus provide a structural basis for a hierarchy in allosteric interactions. A thorough analysis of the isolated tetramer indicates that it functions as a trimer of cooperatively interacting subunits and a non-cooperative monomer rather than as four interacting subunits. A thermodynamic analysis of the whole molecule favors the application of a nested Monod-Wyman-Changeux model with six cooperatively interacting 12-mer allosteric units. In contrast to the isolated tetramers, all subunits of the tetramers seem to be coupled cooperatively within the oligomerized 144-mer. Thus, besides hemocyanins and GroEL, the hexagonal bilayer hemoglobins represent another class of proteins in which the hierarchical quaternary structure provides the basis for nested interaction in their functional properties.
Highlights
In contrast to vertebrate animals that possess tetrameric hemoglobins in red blood cells and monomeric myoglobin in muscle cells, many invertebrates have extracellular hemoglobins with enormously high molecular weights
Based on electron microscopic and structural analyses, the extracellular hemoglobins of annelids exhibit unique structures that constitute the summit of complexity for oxygen-binding hemes. These proteins exhibit variable heterotropic and homotropic interactions: Bohr effects and cooperativity between the heme groups, respectively, that modulate oxygen transport for a given difference in oxygen tensions at the sites of oxygen loading and unloading. They consist of hexagonal bilayer (HBL)1 molecules composed of two superimposed rings that each contain six dodecamers, each comprising three tetramers (12 oxygen-binding heme groups) as well as a number of heme-free “linker” chains that tether the structure (1–5)
When oxygen binding curves of 144-mer HBL from M. decora were analyzed on the basis of the MWC model, the size of the allosteric unit was found to be 7–16 depending on the experimental conditions and weighting of the data points in the fitting procedure (8)
Summary
In contrast to vertebrate animals that possess tetrameric hemoglobins in red blood cells and monomeric myoglobin in muscle cells, many invertebrates have extracellular hemoglobins with enormously high molecular weights. Based on electron microscopic and structural analyses, the extracellular hemoglobins of annelids exhibit unique structures that constitute the summit of complexity for oxygen-binding hemes These proteins exhibit variable heterotropic and homotropic interactions: Bohr effects and cooperativity between the heme groups, respectively, that modulate oxygen transport for a given difference in oxygen tensions at the sites of oxygen loading (gills) and unloading (metabolizing tissues). They consist of hexagonal bilayer (HBL) molecules composed of two superimposed rings that each contain six dodecamers, each comprising three tetramers (12 oxygen-binding heme groups) as well as a number of heme-free “linker” chains that tether the structure (1–5). In view of the complex quaternary structure of HBLs, we analyzed the oxygen binding curves of the whole 144-mer molecules and the isolated tetramers of M. decora in terms of both the two-state MWC model (11) and the nested MWC model, which takes into account the hierarchies within in the quaternary structure (14, 15)
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