Hemoglobin Brockton Beta138

 

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The Brockton hemoglobin (beta 138 (H16) Ala----Pro) variant is an unstable mutant associated with mild anemia. X-ray crystallographic studies show that the substitution does not disrupt critical hydrogen and salt interactions or buried water structures in the H-helix, but it does decrease oxygen affinity.

Documentation

Hemoglobin Brockton [beta 138 (H16) Ala----Pro] is an unstable variant found in members of two unrelated black families with sickle cell disease. The abnormal instability of this variant 138 results from the replacement of tyrosine at beta 35 by phenylalanine, an essential amino acid for the formation of the polar hydrogen bonds and salt bridges in the beta carboxyl-terminal dipeptide. X-ray crystallographic studies suggest that the consequences of the beta 138 Ala----Pro substitution are almost entirely confined to the immediate vicinity of the mutation site. Oxygen affinity measurements indicate that this unstable variant has normal oxygen binding properties. Moreover, electrophoretic mobility on cellulose acetate and hemolysate does not distinguish this variant from Hb A.

Recent structures of activin class cytokine receptors have provided foundational knowledge about how they bind different ligands and elicit a range of cellular responses. These structural studies also enabled comparisons between mutated and wild-type receptors to understand how specific mutations alter the kinase activity of each receptor.

The structure of a hemoglobin variant with decreased oxygen affinity, Hb Brockton [beta 138 (H16) Ala----Pro], revealed that substitution of proline for asparagine at position 138 disrupts critical inter and intrasubunit hydrogen bonds that contribute to the cooperative oxygenation mechanism of normal hemoglobin. Hemoglobin variants with similar oxygen affinity, such as Hb Stanmore [beta 111 (G13) Val----Ala], have not been studied to determine the extent of the disruption of these polar interactions. However, both hemoglobin variants show low intrinsic oxygen affinity. Consequently, their clinical consequences are likely similar to that of Hb Brockton.