Journal
JOURNAL OF MOLECULAR RECOGNITION
Volume 26, Issue 2, Pages 76-85Publisher
WILEY
DOI: 10.1002/jmr.2250
Keywords
heparin; heparan sulfate; integrin; molecular docking; interaction
Categories
Funding
- IXXI (Institut Rhone-Alpin des Systemes Complexes)
- Pole de Competitivite MEDICEN as part of the DOSCA FUI project
- [ANR-07-NANO-050-03]
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Heparin/heparan sulfate interact with growth factors, chemokines, extracellular proteins, and receptors. Integrins are alpha beta heterodimers that serve as receptors for extracellular proteins, regulate cell behavior, and participate in extracellular matrix assembly. Heparin binds to RGD-dependent integrins (alpha IIb beta 3, alpha 5 beta 1, alpha v beta 3, and alpha v beta 5) and to RGD-independent integrins (alpha 4 beta 1, alpha X beta 2, and alpha M beta 2), but their binding sites have not been located on integrins. We report the mapping of heparin binding sites on the ectodomain of alpha v beta 3 integrin by molecular modeling. The surface of the ectodomain was scanned with small rigid probes mimicking the sulfated domains of heparan sulfate. Docking results were clustered into binding spots. The best results were selected for further docking simulations with heparin hexasaccharide. Six potential binding spots containing lysine and/or arginine residues were identified on the ectodomain of alpha v beta 3 integrin. Heparin would mostly bind to the top of the genu domain, the Calf-I domain of the alpha subunit, and the top of the beta subunit of RGD-dependent integrins. Three spots were close enough from each other on the integrin surface to form an extended binding site that could interact with heparin/heparan sulfate chains. Because heparin does not bind to the same integrin site as protein ligands, no steric hindrance prevents the formation of ternary complexes comprising the integrin, its protein ligand, and heparin/heparan sulfate. The basic amino acid residues predicted to interact with heparin are conserved in the sequences of RGD-dependent but not of RGD-independent integrins suggesting that heparin/heparan sulfate could bind to different sites on these two integrin subfamilies. Copyright (C) 2013 John Wiley & Sons, Ltd.
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