Structural basis for the antipolymer activity of Hb ζ2ßs2 trapped in a tense conformation.
J Mol Struct
; 1099: 99-107, 2015 Nov 05.
Article
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| MEDLINE
| ID: mdl-26207073
ABSTRACT
The phenotypical severity of sickle-cell disease (SCD) can be mitigated by modifying mutant hemoglobin S (Hb S, Hb α2ßs2) to contain embryonic ζ-globin in place of adult α-globin subunits (Hb ζ2ßs2). Crystallographical analyses of liganded Hb ζζ2ßs2, though, demonstrate a tense (T-state) quaternary structure that paradoxically predicts its participation in--rather than its exclusion from--pathological deoxyHb S polymers. We resolved this structure-function conundrum by examining the effects of αâζ exchange on the characteristics of specific amino acids that mediate sickle polymer assembly. Superposition analyses of the ßs subunits of T-state deoxyHb α2ßs2 and T-state CO-liganded Hb ζ2ßs2 reveal significant displacements of both mutant ßsVal6 and conserved ß-chain contact residues, predicting weakening of corresponding polymer-stabilizing interactions. Similar comparisons of the α- and ζ-globin subunits implicate four amino acids that are either repositioned or undergo non-conservative substitution, abrogating critical polymer contacts. CO-Hb ζ2ßs2 additionally exhibits a unique trimer-of-heterotetramers crystal packing that is sustained by novel intermolecular interactions involving the pathological ßsVal6, contrasting sharply with the classical double-stranded packing of deoxyHb S. Finally, the unusually large buried solvent-accessible surface area for CO-Hb ζ2ßs2 suggests that it does not co-assemble with deoxyHb S in vivo. In sum, the antipolymer activities of Hb ζ2ßs2 appear to arise from both repositioning and replacement of specific α- and ßs-chain residues, favoring an alternate T-state solution structure that is excluded from pathological deoxyHb S polymers. These data account for the antipolymer activity of Hb ζ2ßs2, and recommend the utility of SCD therapeutics that capitalize on α-globin exchange strategies.
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MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2015
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Article