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

Content Provider	Springer Nature Link
Author	Srinivasulu, Sonati Perumalsamy, Krishnaveni Upadhya, Rajendra Manjula, Belur N. Feiring, Steven Alami, Raouf Bouhassira, Eric Fabry, Mary E. Nagel, Ronald L. Acharya, A. Seetharama
Copyright Year	2006
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 α$_{2}$β 2 T87Q mutations as the prototype of three distinct classes of contact sites of deoxy HbS fiber. Binary mixture experiments established that β$^{A}$-chain with the Thr-87 (β)→Gln mutation is as potent as the γ-chain of HbF (α$_{2}$γ$_{2}$) 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.
Starting Page	503
Ending Page	516
Page Count	14
File Format	PDF
ISSN	15723887
Journal	The Protein Journal
Volume Number	25
Issue Number	7-8
e-ISSN	15734943
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2006-11-28
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Sickle cell disease Linkage of mutations Synergy Neutralization gene therapy Animal Anatomy / Morphology / Histology Organic Chemistry Biochemistry Bioorganic Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Analytical Chemistry Biochemistry Bioengineering

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