Evolution of Myoglobin / Hemoglobin Proteins

Protein Evolution - Figure 5.14 compares the amino acid sequences of sperm whale myoglobin and human myoglobin. Out of the 153 amino acids in both myoglobins, there are only 25 differences, thus 25 amino acid changes have arisen since sperm whales and humans diverged from a common mammalian ancestor about 100 million years ago. For human and shark myoglobin, on the other hand, about 88 differences have arisen since their evolutionary lines diverged about 400 million years ago. The number of amino acid substitutions in two related proteins is roughly proportional to the evolutionary time that has elapsed since the proteins (and the species) had a common ancestor. Using this principle, and comparing the sequences of both hemoglobins and myoglobins one can construct a "family tree" of the globin proteins (Figure 7.23). The tree is complicated by the fact that higher eukaryotes, including humans, carry genes for both myoglobin and several different hemoglobin chains (see here).

Primitive Globin - Very primitive animals had only a myoglobin-like, single-chain ancestral globin for oxygen storage and were so small that they did not require a transport protein. Roughly 500 million years ago the ancestral myoglobin gene was duplicated. One copy became the ancestor of the myoglobin genes of all higher organisms. The other copy evolved into the gene for an oxygen transport protein and gave rise to the hemoglobins.

Most Primitive Hemoglobin - The most primitive animals to possess hemoglobin are the lampreys. Lamprey hemoglobin can form dimers but not tetramers and is only weakly cooperative. It represents a first step toward allosteric binding. Subsequently a second gene duplication must have occurred, giving rise to the ancestors of the present-day and hemoglobin chain families. This must have happened about 400 million years ago, at about the time of divergence of the sharks and bony fish. The evolutionary line of the bony fish led to the reptiles and eventually to the mammals, all carrying genes for both and globins and capable of forming tetrameric 2 2 hemoglobins. Further gene duplications have occurred in the hemoglobin line, leading to the embryonic forms and , the fetal form, , and the infant form (Figure 7.22).

Conserved Amino Acid Sequences - During the long evolution of the myoglobin/hemoglobin family of proteins, only a few amino acid residues have remained invariant (Figure 7.11). They include the histidines proximal and distal to the heme iron (F8 and E7- see Figure 7.5b) and Val FG5, which has been implicated in the hemoglobin deoxy/oxy conformation change. These may mark the truly essential positions in the molecule. Other regions highly conserved in hemoglobins are those near the 1 - 2 and 2 - 1 contacts. These parts of the molecule are most directly involved in the allosteric conformational change.

Backbone Structures - Figure 7.24 shows the backbone structure of members of the myoglobin/hemoglobin family, ranging from insect to horse. It reveals that the secondary and tertiary structures of these proteins have remained surprisingly constant, despite the major changes in primary structure (amino acid sequence) changes that have occurred over hundreds of millions of years. Survival of mutant proteins in the globin family has been restricted to those that maintain the basic "globin fold."

See also: Globin Gene Expression in Development, Mechanisms of Protein Mutation, Hemoglobin Variants

INTERNET LINK: Globin Gene Server