Reversible binding of hemoglobin to band 3 constitutes the molecular switch that mediates O2 regulation of erythrocyte properties.
Functional studies have shown that the oxygenation state of the erythrocyte regulates many important pathways, including glucose metabolism, membrane mechanical stability, and cellular adenosine triphosphate (ATP) release. Deoxyhemoglobin (deoxyHb), but not oxyhemoglobin, binds avidly and reversibly to band 3, the major erythrocyte membrane protein. Because band 3 associates with multiple metabolic, solute transport, signal transduction, and structural proteins, the hypothesis naturally arises that the O2-dependent regulation of erythrocyte properties might be mediated by the reversible association of deoxyHb with band 3. To explore whether the band 3-deoxyHb interaction constitutes a "molecular switch" for regulating erythrocyte biology, we have generated transgenic mice with mutations in the deoxyHb-binding domain of band 3. One strain of mouse contains a "humanized" band 3 in which the N-terminal 45 residues of mouse band 3 are replaced by the homologous sequence from human band 3, including the normal human band 3 deoxyHb-binding site. The second mouse contains the same substitution as the first, except the deoxyHb site on band 3 (residues 12-23) has been deleted. Comparison of these animals with wild-type mice demonstrates that the following erythrocyte properties are controlled by the O2-dependent association of hemoglobin with band 3: (1) assembly of a glycolytic enzyme complex on the erythrocyte membrane which is associated with a shift in glucose metabolism between the pentose phosphate pathway and glycolysis, (2) interaction of ankyrin with band 3 and the concomitant regulation of erythrocyte membrane stability, and (3) release of ATP from the red cell which has been linked to vasodilation.
Department of Chemistry, Purdue University, West Lafayette, IN; and.
Haiyan
0000-0002-8004-8033
H
Chu
Genetics and Molecular Biology Branch, National Human Genome Research Institute.
Mary M
MM
McKenna
Genetics and Molecular Biology Branch, National Human Genome Research Institute.
Nathan A
NA
Krump
Department of Chemistry, Purdue University, West Lafayette, IN; and.
Suilan
S
Zheng
Sickle Cell Branch, National Heart, Lung, and Blood Institute, and.
Laurel
L
Mendelsohn
Sickle Cell Branch, National Heart, Lung, and Blood Institute, and.
Swee Lay
SL
Thein
Embryonic Stem Cell and Transgenic Mouse Core Facility, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Lisa J
LJ
Garrett
Genetics and Molecular Biology Branch, National Human Genome Research Institute.
David M
DM
Bodine
Department of Chemistry, Purdue University, West Lafayette, IN; and.
Philip S
PS
Low
D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics / Q000378:metabolism*; D004910:Erythrocyte Membrane / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism*; D010108:Oxyhemoglobins / Q000235:genetics / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000502:physiology
D001457:Anion Exchange Protein 1, Erythrocyte; D010108:Oxyhemoglobins; C523515:Slc4a1 protein, mouse; D010100:Oxygen
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