Inhibition of sickle beta-chain (betaS)-dependent polymerization by nonhuman alpha-chains. A superinhibitory mouse-horse chimeric alpha-chain.
Horse alpha-chain inhibits sickle beta-chain-dependent polymerization; however, its inhibitory potential is not as high as that of mouse alpha-chain. Horse alpha-(1-30) and alpha-(31-141) segments make, respectively, minor and major contributions to the inhibitory potential of horse alpha-chain. The sum of the inhibitory potential of the two segments does not account for the inhibitory potential of the full-length horse alpha-chain. Although the polymerization inhibitory potential of horse alpha-chain is lower than mouse alpha-chain, the inhibitory potential of horse alpha-(31-141) is comparable to that of mouse alpha-(31-141). When mouse alpha-(1-30) is stitched to horse alpha-(31-141), the product is a chimeric alpha-chain with an inhibitory potential greater than mouse alpha-chain. In contrast, the stitching of horse alpha-(1-30) with mouse alpha-(31-141) had no additional inhibitory potential. Molecular modeling studies of HbS containing the mouse-horse chimeric alpha-chain indicate altered side-chain interactions at the alpha1beta1 interface when compared with HbS. In addition, the AB/GH corner perturbations facilitate a different stereochemistry for the interaction of the epsilon-amino group of Lys-16(alpha) with the beta-carboxyl group of Asp-116(alpha), resulting in a decrease in the accessibility of the side chain of Lys-16(alpha) to the solvent. Based on molecular modeling, we speculate that these perturbations by themselves, or in synergy with the altered conformational aspects of the alpha1beta1 interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric alpha-chains.
Nacharaju
P
P
Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
Roy
R P
RP
White
S P
SP
Nagel
R L
RL
Acharya
A S
AS
D000818:Animals; D001704:Biopolymers; D002384:Catalysis; D002852:Chromatography, Ion Exchange; D006451:Hemoglobin, Sickle / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006736:Horses; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
D001704:Biopolymers; D006451:Hemoglobin, Sickle; D011993:Recombinant Fusion Proteins; D010100:Oxygen