Ann Taylor/Hemoglobin
From Proteopedia
Hemoglobin is an oxygen-transport protein. Hemoglobin is an allosteric protein. It is a tetramer composed of two types of subunits designated α and β, with stoichiometry . The of hemoglobin sit roughly at the corners of a tetrahedron, facing each other across a at the center of the molecule. Each of the subunits prosthetic group. The give hemoglobin its red color. The α and β subunits have very similar structures, despite their sequence differences. We will use a single to examine the subunit structure more closely. The 6 major and 2 short α-helices that make up the structure of a Hb subunit (the "globin fold") are , which is the traditional naming scheme. The helices form an approximately-cylindrical bundle, with the heme and its central Fe atom bound in a (hydrophobic = grey; hydrophilic = purple). The proximal histidine (the tightest protein-Fe intraction) is often called , since it is residue 9 on helix F (it is residue 87 in the human α chain). A second histidine is near the bound oxygen, and is referred to as the . In the deoxy state, the Fe2+ is of the porphyrin ring. When oxygen is bound, the iron changes spin state, resulting in the iron moving of the heme. made by Alexander Berchansky shows the oxy (in pink) and deoxy (in deepskyblue) α1 heme groups were superimposed on each other, to give a local comparison at this site, a closeup around the heme O2-binding site. The heme is quite domed in the deepskyblue T-state (deoxy) form, with the 5-coordinate, high-spin Fe (orange ball) out of the plane. In the pink R-state form a CO molecule is bound at the right (C in green,O in red); the Fe, now 6-coordinate low-spin, has moved into the heme plane, which has flattenened. The proximal His (at left) connects the Fe to helices on the proximal side, making the Fe position sensitive to changes in the globin structure and vice versa. Remember that this scene shows a subunit in the all-unliganded versus the all-liganded states of Hb; when oxygen binds to just one subunit, then its internal structure undergoes some but not all of these changes, depending on conditions. Perhaps the most well-known disease caused by a mutation in the hemoglobin protein is sickle-cell anemia. It results from a mutation of the sixth residue in the β hemoglobin monomer from . This hemoglobin variant is called 'hemoglobin S' (2hbs).
T to R transitionFor hemoglobin to function as an oxygen-carrier in the blood, it must have an equilibrium between the two main states of its quaternary structure, the unliganded "deoxy" or "T state" versus the liganded "oxy" or "R state". The unliganded (deoxy) form is called the "T" (for "tense") state because it contains extra stabilizing interactions between the subunits, specifically . In the high oxygen affinity R-state conformation, these ionic interactions , and the tetramer is described as "relaxed". In some organisms this difference is so pronounced that their Hb molecules dissociate into dimers in the oxygenated form. Structural changes that occur during this transition can illuminate how such changes result in important functional properties, such as cooperativity of oxygen binding and allosteric control by pH and anions. The Bohr effect is the increased stability of the T state due to protonation of histidine residues, especially of the beta chains. This is the C terminal residue of the beta chain. In the T state, the C terminal carboxylate group interacts with the positively charged side chain of lysine 40 of an alpha chain. When His 146 is protonated, it can also form an ionic interaction with Asp 94. This second interaction is one of several interactions which stabilizes the T state at lower pH. Bisphosphoglycerate (BPG) is a biproduct of metabolism; its presence is an indication of increased need for oxygen in the tissues. It binds in the of hemoglobin, but only in the deoxy (T) state. The binding is due to interactions with . In the oxy form, this cavity is much narrower, and BPG cannot bind. Some fish exhibit a more extreme stabilization at low pH, to the extent that the fully oxygenated species cannot be generated at atmospheric oxygen concentrations. [1] This is due to several ionic interactions not found in the human or mammalian hemoglobins. A novel salt bridge is found between His-69 and Asp-72 of the beta chains in the T state. Furthermore, and Asn99α2 in the T state but not the R state. Additional proton binding to the T state occurs through a pair of carboxyl groups, . These groups share a proton in the T state that is lost in the R state as the two αβ dimers rotate, pulling the carboxyl side chains apart, allowing them to both have a negative charge. Interestingly, no salt bridge is formed by His-146 at C terminus of the beta chain, in contrast to the Bohr effect seen in human hemoglobin and described above. This may be because the serine at position 93 is changed to a cysteine in Tuna, which seems to prevent this interaction rather than strengthen it. References
Content DonatorsMuch of this page's content originally came from the Hemoglobin page. Many thanks to Alexander Berchansky for the hemoglobin animation. To ensure stability during my class and to include some specific data we will be using in a paper discussion, this page was created. | |||||||||||
