Inhibition of sickle β-Chain (βS)-dependent polymerization by nonhuman α-chains

Nacharaju, Parimala ; Roy, Rajendra Prasad ; White, Steven P. ; Nagel, Ronald L. ; Seetharama Acharya, A. (1997) Inhibition of sickle β-Chain (βS)-dependent polymerization by nonhuman α-chains Journal of Biological Chemistry, 272 (44). pp. 27869-27876. ISSN 0021-9258

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Horse α-chain inhibits sickle β-chain-dependent polymerization; however, its inhibitory potential is not as high as that of mouse α-chain. Horse α-(1-30) and α-(31-141) segments make, respectively, minor and major contributions to the inhibitory potential of horse α-chain. The sum of the inhibitory potential of the two segments does not account for the inhibitory potential of the full-length horse α-chain. Although the polymerization inhibitory potential of horse α-chain is lower than mouse α-chain, the inhibitory potential of horse α-(31-141) is comparable to that of mouse α-(31-141). When mouse α-(1-30) is stitched to horse α-(31-141), the product is a chimeric α-chain with an inhibitory potential greater than mouse α-chain. In contrast, the stitching of horse α-(1-30) with mouse α-(31-141) had no additional inhibitory potential. Molecular modeling studies of HbS containing the mouse-horse chimeric α-chain indicate altered side-chain interactions at the α1β1 interface when compared with HbS. In addition, the AB/GH corner perturbations facilitate a different stereochemistry for the interaction of the ε-amino group of Lys-16(α) with the β-carboxyl group of Asp-116(α), resulting in a decrease in the accessibility of the side chain of Lys-16(α) to the solvent. Based on molecular modeling, we speculate that these perturbations by themselves, or in synergy with the altered conformational aspects of the α1β1interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric α-chains.

Item Type:Article
Source:Copyright of this article belongs to The American Society for Biochemistry and Molecular Biology.
ID Code:52408
Deposited On:03 Aug 2011 14:03
Last Modified:03 Aug 2011 14:03

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