TY - JOUR
T1 - Inhibition of sickle β-chain (β(S))-dependent polymerization by nonhuman α-chains
T2 - A superinhibitory mouse-horse chimeric α-chain
AU - Nacharaju, Parimala
AU - Roy, Rajendra Prasad
AU - White, Steven P.
AU - Nagel, Ronald L.
AU - Acharya, A. Seetharama
PY - 1997/10/31
Y1 - 1997/10/31
N2 - 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 aα1β1 interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric α- chains.
AB - 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 aα1β1 interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric α- chains.
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U2 - 10.1074/jbc.272.44.27869
DO - 10.1074/jbc.272.44.27869
M3 - Article
C2 - 9346934
AN - SCOPUS:0030783254
SN - 0021-9258
VL - 272
SP - 27869
EP - 27876
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -