Sickle hemoglobin, aggregation

Thus, the aggregates of sickle hemoglobin tetramers must be reasonably spherical, on the basis of the measurements of macroscopic viscosity (16) and not too large, but nonetheless present, on the basis of the NMRD results. 

As an example of the way in which the code is read. Fig. 2 shows small sections from the normal and a mutated form of the P-globin gene (see p. 280), as well as the corresponding mRNA and protein sequences. The point mutation shown, which is relatively frequent, leads to replacement of a glutamate residue in position 6 of the p-chain by valine (GAG GTG). As a consequence, the mutated hemoglobin tends to aggregate in the deoxy-genated form. This leads to sickle-shaped dis-... 

Figure 9 shows force laws for phosphatidylcholine bilayers (Lis et al, 1982), determined by the osmotic stress method. Similar data were obtained for DNA samples (Rau et al., 1984). The characteristic length governing decay of the force is about 3 A for both systems. Interactions of this kind can also be important for protein aggregates. Prouty et al. (1985) used the osmotic stress method to determine the phase diagram of sickle cell hemoglobin (Fig. 10). At a critical osmotic pressure, which is temperature dependent, a solution of deoxyhemoglobin S collapses to a gel, with a large change in volume. One of the strengths of the osmotic stress method is that it provides additional information that can be used for thermodynamic analysis of the system.

Hemoglobin dramatically demonstrates how sensitive the function of a biomolecule is to its structure. In certain people, in the synthesis of the proteins needed for hemoglobin, an improper amino acid is inserted into the protein in two places. This may not seem very serious, since there are several hundred amino acids present. However, because the incorrectly inserted amino acid has a nonpolar substituent instead of the polar one found on the proper amino acid, the hemoglobin drastically changes its shape. The red blood cells are then sickle-shaped rather than disk-shaped, as shown in Fig. 20.37. The misshapen cells can aggregate, causing clogging of tiny capillaries. This condition, known as sickle cell anemia, is the subject of intense research. 

Val 1-NAl, Lys 82-EF6, and His 143-H21) and deoxy Hb-S does not produce configuration changes which influence the aggregation of the molecules (B35). Moreover, cyanate (HN=C=0) which carbamylates amino terminal residues of proteins (R—NH—CO—NH2) is an effective inhibitor of sickling of erythrocytes in vitro and of gelling of concentrated solutions of deoxyhemoglobin S (C9). Addition of some specific hemoglobin variants, Hb-O-Arab or 02 2 (M16) and Hb-Korle Bu... 

What kind of intermolecular forces are responsible for the aggregation of hemoglobin molecules that leads to sickle cell anemia Hint See the Chemistry in Action essay on p. 985.)... 

HbS, a2b26Glu Val. The nomenclature means that the sixth residue in the b-chain (normally a Glu) has been replaced by Val. Hemoglobin S is found in people with sickle-cell anemia. As expected for a polar residue, Glu-6 is on the outside of the molecule. Insertion of a valine here would be expected to reduce the solubility of hemoglobin and encourage aggregation. 

Sickle-cell anemia Defective hemoglobin sickled red blood cells aggregate to cause anemia, plugged capillaries, low oxygen pressure in tissues. 

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