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 E. Bouhassira, Mary E. Fabry, Ronald L. Nagel, A. Seetharama Acharya

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 2006

Fingerprint

Sickle Hemoglobin
Hemoglobin
Polymerization
Dimers
Binary mixtures
Mutation
Gene therapy
Fibers
Experiments
Sickle Cell Anemia
Genetic Therapy

Keywords

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

ASJC Scopus subject areas

  • Biochemistry

Cite this

Srinivasulu, S., Perumalsamy, K., Upadhya, R., Manjula, B. N., Feiring, S., Alami, R., ... 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

Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S. / Srinivasulu, Sonati; Perumalsamy, Krishnaveni; Upadhya, Rajendra; Manjula, Belur N.; Feiring, Steven; Alami, Raouf; Bouhassira, Eric E.; Fabry, Mary E.; Nagel, Ronald L.; Acharya, A. Seetharama.

In: Protein Journal, Vol. 25, No. 7-8, 12.2006, p. 503-516.

Research output: Contribution to journalArticle

Srinivasulu, S, Perumalsamy, K, Upadhya, R, Manjula, BN, Feiring, S, Alami, R, Bouhassira, EE, Fabry, ME, Nagel, RL & Acharya, AS 2006, 'Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S', Protein Journal, vol. 25, no. 7-8, pp. 503-516. https://doi.org/10.1007/s10930-006-9034-3
Srinivasulu S, Perumalsamy K, Upadhya R, Manjula BN, Feiring S, Alami R et al. Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S. Protein Journal. 2006 Dec;25(7-8):503-516. https://doi.org/10.1007/s10930-006-9034-3
Srinivasulu, Sonati ; Perumalsamy, Krishnaveni ; Upadhya, Rajendra ; Manjula, Belur N. ; Feiring, Steven ; Alami, Raouf ; Bouhassira, Eric E. ; Fabry, Mary E. ; Nagel, Ronald L. ; Acharya, A. Seetharama. / Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S. In: Protein Journal. 2006 ; Vol. 25, No. 7-8. pp. 503-516.
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AU - Feiring, Steven

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