Functional characterization of ECP-heparin interaction: a novel molecular model

PloS One
Ta-Jen HungMargaret Dah-Tsyr Chang

Abstract

Human eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) are two ribonuclease A (RNaseA) family members secreted by activated eosinophils. They share conserved catalytic triad and similar three dimensional structures. ECP and EDN are heparin binding proteins with diverse biological functions. We predicted a novel molecular model for ECP binding of heparin hexasaccharide (Hep6), [GlcNS(6S)-IdoA(2S)]3, and residues Gln(40), His(64) and Arg(105) were indicated as major contributions for the interaction. Interestingly, Gln(40) and His(64) on ECP formed a clamp-like structure to stabilize Hep6 in our model, which was not observed in the corresponding residues on EDN. To validate our prediction, mutant ECPs including ECP Q40A, H64A, R105A, and double mutant ECP Q40A/H64A were generated, and their binding affinity for heparins were measured by isothermal titration calorimetry (ITC). Weaker binding of ECP Q40A/H64A of all heparin variants suggested that Gln(40)-His(64) clamp contributed to ECP-heparin interaction significantly. Our in silico and in vitro data together demonstrate that ECP uses not only major heparin binding region but also use other surrounding residues to interact with heparin. Such correlation ...Continue Reading

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Citations

Jul 1, 2014·Journal of Chemical Information and Modeling·Scott E MottarellaSandor Vajda

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Methods Mentioned

BETA
X-ray
NMR
electrophoresis
enzyme-link immunosorbent assay
ELISA
affinity column chromatography
cleavage assay
isothermal titration calorimetry

Software Mentioned

MicroCal Origin
GraphPad
AutoDock Vina
Clustal X2
AutoDock
GROMOS
GraphPad Prism

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