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Familial secondary erythrocytosis due to increased oxygen affinity is caused by destabilization of the T state of hemoglobin Brigham (α₂β₂(Pro100Leu)).

Authors :
Mollan TL
Abraham B
Strader MB
Jia Y
Lozier JN
Olson JS
Alayash AI
Source :
Protein science : a publication of the Protein Society [Protein Sci] 2012 Oct; Vol. 21 (10), pp. 1444-55. Date of Electronic Publication: 2012 Aug 21.
Publication Year :
2012

Abstract

Hemoglobin Brigham (β Pro100 to Leu) was first reported in a patient with familial erythrocytosis. Erythrocytes of an affected individual from the same family contain both HbA and Hb Brigham and exhibit elevated O₂ affinity compared with normal cells (P₅₀ = 23 mm Hg vs. 31 mmHg at pH 7.4 at 37°C). O₂ affinities measured for hemolysates were sensitive to changes in pH or chloride concentrations, indicating little change in the Bohr and Chloride effects. Hb Brigham was separated from normal HbA by nondenaturing cation exchange liquid chromatography, and the amino acid substitution was verified by mass spectrometry. The properties of Hb Brigham isolated from the patient's blood were then compared with those of recombinant Hb Brigham expressed in Escherichia coli. Kinetic experiments suggest that the rate constants for ligand binding and release in the high (R) and low (T) affinity quaternary states of Hb Brigham are similar to those of native hemoglobin. However, the Brigham mutation decreases the T to R equilibrium constant (L) which accelerates the switch to the R state during ligand binding to deoxy-Hb, increasing the rate of association by approximately twofold, and decelerates the switch during ligand dissociation from HbO₂, decreasing the rate approximately twofold. These kinetic data help explain the high O₂ affinity characteristics of Hb Brigham and provide further evidence for the importance of the contribution of Pro100 to intersubunit contacts and stabilization of the T quaternary structure.<br /> (Copyright © 2012 The Protein Society.)

Details

Language :
English
ISSN :
1469-896X
Volume :
21
Issue :
10
Database :
MEDLINE
Journal :
Protein science : a publication of the Protein Society
Publication Type :
Academic Journal
Accession number :
22821886
Full Text :
https://doi.org/10.1002/pro.2130