Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S

Sonati Srinivasulu, Krishnaveni Perumalsamy, Rajendra Upadhya, Belur N. Manjula, Steven Feiring, Raouf Alami, Eric Bouhassira, Mary E. Fabry, Ronald L. Nagel, A. Seetharama Acharya

Research output: Contribution to journalArticle

5 Scopus citations

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 languageEnglish (US)
Pages (from-to)503-516
Number of pages14
JournalProtein Journal
Volume25
Issue number7-8
DOIs
StatePublished - Dec 1 2006

Keywords

  • Linkage of mutations
  • Neutralization gene therapy
  • Sickle cell disease
  • Synergy

ASJC Scopus subject areas

  • Analytical Chemistry
  • Bioengineering
  • Biochemistry
  • Organic Chemistry

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    Srinivasulu, S., Perumalsamy, K., Upadhya, R., Manjula, B. N., Feiring, S., Alami, R., Bouhassira, E., Fabry, M. E., Nagel, R. L., & Acharya, A. S. (2006). Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S. Protein Journal, 25(7-8), 503-516. https://doi.org/10.1007/s10930-006-9034-3