Hemoglobin Transport Protein

Jordan Levin '19


I. Introduction

Hemoglobin is an oxygen transport protein found in vertebrates. The transport protein is crucial for life of multi cellular organisms that require a constant availability of oxygen for cellular respiration. Hemoglobin is found in red blood cells binding to four oxygen molecules in the lungs and transports them to the tissues.

Hemoglobin is not only an oxygen binding protein, it plays a key role in the respiratory pathway which includes binding to carbon dioxide once oxygen is released. The carbon dioxide gets transported from the tissues to the lungs, then exhaled out of the body. Hemoglobin can also bind to carbon monoxide and nitric oxide.  

II. General Structure

The human hemoglobin protein is made up of four subunits, two identical alpha subunits ( A and C , 141 residues) and two identical beta subunits ( B and D , 146 residues). Each subunit binds to a which contains an iron ion in the center and is responsible for binding to oxygen.

III. Oxygen Binding

Although there are multiple carbon ritch residues that bind to the heme by Van der Waals interations, histidine 87 directly attaches to the central iron ion in the heme group by a coordinate covalent bond . Electrostatic interactions explain polarity of heme binding pocket . The binding pocket and the heme group go through a conformational change when oxygen binds to the heme. The heme has a domed configuration when it is deoxygenated but when oxygen is present it adopts a planar configuration. These two configurations are known as the T or tense structure where the protein has a low affinity for oxygen and the R or relaxed structure where oxygen binds with higher affinity. Hemoglobin oxygen binding is classified as cooperative binding meaning that once one oxygen is bound to a heme, the other three hemes have a higher affinity for oxygen. There is a conformational change throughout the protein making the iron ion in the heme group more accessible to oxygen. The change from T to R shifts the alpha and beta F helices one angstrom and the beta E helix two angstroms, opening the oxygen binding pockets. Specifically, valine 67 on the beta E helices, which blocks oxygen binding in the 'T' state, is moved to increase oxygen affinity.

IV. Regulation

Once the oxygen is bound to the hemoglobin it is moved via blood in the arteries. Regulation of hemoglobin occurs in an acidic environment where allosteric inhibition triggers the release of oxygen. The acidic environment is caused by carbonic acid which is concentrated in high cellular respiration areas. Carbon dioxide is produced as a byproduct of cellular respiration and in the presence of water, produces carbonic acid and hydrogen ions. The Bohr effect explains that hemoglobin has a lower affinity for oxygen when the pH is low and a higher affinity for oxygen when the pH is high.

V. Sickle Cell Anemia

Sickle cell anemia is caused by a genetic point mutation on residue 6 of both beta subunits. Wild type hemoglobin has a glutamate on position 6 but the mutated hemoglobin has a valine. The residue change from a polar sidechain to non polar is the basis of sickle cell aggregation. The nonpolar valine can form Van der Waals interactions with either a luecine on residue 88 or phenylalanine on residue 85 of an adjacent deoxygenated beta subunit of hemoglobin. This same interaction can form long polymer fibers within a red blood cell creating the sickle cell shape. These mutated red blood cells can easily clog capillaries resulting in painful swelling and reduced blood circulation.

VI. References

Fermi, G., Perutz, M. F., Shaanan, B. 1983. The Crystal Structure of Human Deoxyhaemoglobin at 1.74 A Resolution. J. Mol. Biol., 159-174.

Harrington, DJ., Adachi, K., Royer, WE Jr. 1997. The High Resolution Crystal Structure of Deoxyhemoglobin S. J Mol Biol., 398-407.

Thomas, Caroline., Lumb, Andrew B. 2012. Physiology of Haemoglobin. Continuing Education in Anesthesia Critical Care and Pain. Vol 12, Issue 5.

Image 1: Traverso, Matt. 2004. Conformational Changes Upon Binding of Oxygen. Washington University in St Louis.

Image 2: Thomas, Caroline., Lumb, Andrew B. 2012. Physiology of Haemoglobin. Continuing Education in Anesthesia Critical Care and Pain. Vol 12, Issue 5.

Image 3: Bohr Effect Oxygen Release Explained: Healthy Vs Sick People. Normal Breathing.

Image 4: Mukerji, Ishita. Understanding Fiber Formation. About Sickle Cell Disease.

Image 5: Dr. Elebute, Modupe. 2016. Sickle Cell Disease. The London Physician.

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