Abstract
The linkage of pair-wise interactions of contact site mutations of HbS has been studied using Le Lamentin [His-20 (α)→Gln], Hoshida [Glu-43 (β)→Gln] and α2β 2 T87Q mutations as the prototype of three distinct classes of contact sites of deoxy HbS fiber. Binary mixture experiments established that βA-chain with the Thr-87 (β)→Gln mutation is as potent as the γ-chain of HbF (α2γ2) in inhibiting polymerization. On combining the influence of Le Lamentin mutation with that of β 2 T87Q mutations; the net influence is only partial additivity. On the other hand, in binary mixture studies, combined influence of Hoshida mutation with that of β 2 T87Q mutations is synergistic. Besides, a significant level of synergistic complementation is also seen when the Le Lamentin and Hoshida mutations are combined in HbS (symmetrical tetramers). Le Lamentin and Hoshida mutation introduced into the cis-dimer of the asymmetric hybrid tetramer completely neutralizes the Val-6 (β) dependent polymerization. Accordingly, we propose that combining the perturbation of intra-double strand contact site with that of an inter-double strand contact site exhibit synergy when they are present in two different chains of the αβ dimer. A comparison of the present results with that of the earlier studies suggest that when the two contact site perturbations are from the same sub-unit of the αβ dimer only partial additivity is observed. The map of interaction linkage of the contact site mutations exposes new strategies in the design of novel anti-sickling Hbs for the gene therapy of sickle cell disease.
Original language | English (US) |
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Pages (from-to) | 503-516 |
Number of pages | 14 |
Journal | Protein Journal |
Volume | 25 |
Issue number | 7-8 |
DOIs | |
State | Published - Dec 2006 |
Keywords
- Linkage of mutations
- Neutralization gene therapy
- Sickle cell disease
- Synergy
ASJC Scopus subject areas
- Analytical Chemistry
- Bioengineering
- Biochemistry
- Organic Chemistry