Question

Explain why the structure of myoglobin makes it function well as an oxygen-storage protein whereas the structure of hemoglobin makes it function well as an oxygen-transport protein. Describe briefly the two principal models for the cooperative binding of ligands to proteins with multiple binding sites.

Answer 1

a) Myoglobin has one heme while haemoglobin has four heme associated with it. Heme is a non protein molecule containing protoporphyrin IX that has an chelated iron atom. It is present in a small hydrophobic pocket in each polypeptide. Myoglobin with its eight alpha helix segments, therefore can bind only to one oxygen. Haemoglobin has four alpha and beta segments that bind four oxygen. Binding of one molecule of oxygen to haemoglobin will increase the affinity of other subunits for three oxygen molecules. Release of one oxygen will result in release of other oxygen too. This is known as co-operativity of haemoglobin.

Myoglobin is present in muscle cell where it acts as an oxygen reservoir. Myoglobin binds to oxygen that is released by haemoglobin and diffuses into the tissues. Myoglobin shows a hyperbolic oxygen dissociation curve while haemoglobin shows a sigmoidal oxygen dissociation curve. The binding of oxygen to the single binding site on myoglobin results in high affinity for oxygen despite the low partial pressure of oxygen that is present in tissues. Further superoxide ion cannot leave the heme group due to the structure of myoglobin. Hence, it tends to store oxygen due to its high affinity for oxygen in tissues as it is relatively insensitive to small fluctuations in oxygen. Myoglobin remains saturated with oxygen at oxygen tensions between 15-30 mm Hg and will release oxygen to muscle mitochondria only at low oxygen tensions.

On the other hand, the binding of oxygen to the multiple binding sites on haemoglobin results in high affinity for oxygen in the lungs but low oxygen affinity in the tissues. Hence, haemoglobin will bind with high affinity to oxygen in the lungs but release oxygen in tissues. Haemoglobin is present in red blood cells that also harbor 2,3 bisphosphoglycerate. 2,3 bisphosphoglycerate can bind to hemoglobin and reduce its affinity for oxygen in blood by stabilizing the T state. Thus, haemoglobin has lower affinity for oxygen than myoglobin.

b) The two principal models for cooperative binding of ligands to proteins with multiple binding sites are

1) Concerted or MYC model and 2) Sequential model

1) Concerted model: This model postulates that binding of one ligand to one site causes a conformational change that converts all remaining subunits to a high affinity conformation. Thus, all subunits will have the same confirmation, whether high or low affinity. This model was used to explain haemoglobin binding wherein the conformation can be R (relaxed) or T (tense ) state. The R (oxyHb) state is flexible for oxygen binding while the T state (deoxyHb). All oxygen have to bind to Haemoglobin in T state to form the R state. Similarly, all oxygen needs to be released from R state to form the T state. This model fails to describe the mechanism of change in shape of haemoglobin shape upon oxygen binding. It also does not explain how adjacent heme groups that are not occupied increase their affinity for hemoglobin.

2) Sequential model: The subunits of the protein are not connected in this model. The binding of ligand to one site does not cause a high affinity conformation in the other sites. Thus, there are different high or low affinity subunits present in the protein in varying combinations. It accounts for different species of protein molecule. This model explains how oxygen exists in different states. It indicates that oxygen has three intermediate state between R and T state. As per this model, the binding of oxygen alters the shape of the subunits. It also alters the nearby subunits causing them to alter the affinity for oxygen. Thus, haemoglobin is in R state only when all four oxygen bind to our heme. However, this does not occur in nature. Haemoglobin can exist in R state even when three oxygen bound to three heme.