1996
DOI: 10.1006/jmbi.1996.0590
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Roles of α114 and β87 Amino Acid Residues in the Polymerization of Hemoglobin S: Implications for Gene Therapy

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Cited by 22 publications
(13 citation statements)
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“…The sixth residue (Pro1 14) is displaced to a greater extent (1.2Å and 1.3Å for the α1/ζ1 and α2/ζ2 superpositions, respectively), predicting a more meaningful impact on the strengths of corresponding hydrogen-bond interactions. The potential contribution of a repositioned Pro114 to the antipolymer activity of CO-Hb ζ 2 β s 2 accords with studies demonstrating that Hb S-variant heterotetramers that incorporate recombinant αPro1 14→Arg substitutions display increased solubility in vitro [50], naturally occurring variants at this position are unusual and have not been reported in patients with sickle syndromes [5153]. Consequently, secondary intermolecular contacts subserved by conserved residues are largely preserved by α→ζ exchange and, with the possible exception of Pro1 14, are likely to promote--rather than to inhibit--inclusion of CO-Hb ζ 2 β s 2 in the deoxyHb S polymer.…”
Section: Resultssupporting
confidence: 67%
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“…The sixth residue (Pro1 14) is displaced to a greater extent (1.2Å and 1.3Å for the α1/ζ1 and α2/ζ2 superpositions, respectively), predicting a more meaningful impact on the strengths of corresponding hydrogen-bond interactions. The potential contribution of a repositioned Pro114 to the antipolymer activity of CO-Hb ζ 2 β s 2 accords with studies demonstrating that Hb S-variant heterotetramers that incorporate recombinant αPro1 14→Arg substitutions display increased solubility in vitro [50], naturally occurring variants at this position are unusual and have not been reported in patients with sickle syndromes [5153]. Consequently, secondary intermolecular contacts subserved by conserved residues are largely preserved by α→ζ exchange and, with the possible exception of Pro1 14, are likely to promote--rather than to inhibit--inclusion of CO-Hb ζ 2 β s 2 in the deoxyHb S polymer.…”
Section: Resultssupporting
confidence: 67%
“…The principle that the pathobiology of deoxyHb S can be mitigated by α- or β-like subunit exchange is founded upon methodologically independent ultrastructrual analyses [5,6,912,59,60], as well as in vitro and in vivo studies of naturally occurring and engineered variant hemoglobins [13,18,22,29,33,34,50,61]. We previously studied the biochemical characteristics of Hb ζ 2 β s 2 , a heterotetramer that is derived from Hb S by replacing its adult α-globin subunits with developmentally related ζ-globin subunits [23,26].…”
Section: Discussionmentioning
confidence: 99%
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“…Plasmids pKShbSc' and pKShgc' containing the T7 promoter directed human β S -globin cDNA and γ-globin cDNA were constructed by respectively placing human β-globin cDNA fragment from pHE7 and Aγ-globin cDNA fragment from pHE9 [37] into pBluescript II after the T7 promoter. A β6 Glu→Val mutation [19] was introduced into β-globin cDNA to produce human β S -globin cDNA in pKShbSc'.…”
Section: Plasmids For Producing Ribozymes and Mrna Substrates In Vitromentioning
confidence: 99%
“…For anti-sickling treatment, this may be more effective because the harmful effect of HbS polymerization is greatly dependent on HbS concentration, thus even a relatively small decrease in HbS concentration may greatly reduce the tendency of HbS polymerization and sickling [17][18][19][20][21]. An additional challenge in therapeutic strategies to increase HbF is that HbF is not uniformally distributed resulting in a subpopulation of cells in which HbF cannot be detected [22].…”
mentioning
confidence: 99%