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Using a GFP-tagged TMEM184A Construct for Confirmation of Heparin Receptor Identity
Published on: February 17, 2017
Molecular interplay between endostatin, integrins, and heparan sulfate
Clément Faye1, Christophe Moreau1, Emilie Chautard1
1Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS-University Lyon 1, IFR 128 Biosciences Gerland Lyon Sud, 7 passage du Vercors, 69367 Lyon Cedex 07, France.
The Journal of Biological Chemistry
|June 9, 2009
Summary
Endostatin, an angiogenesis inhibitor, binds to integrins alpha5beta1 and alphavbeta3. Key arginine residues are vital for these interactions and binding to heparin, influencing endostatin
Area of Science:
- Biochemistry and Molecular Biology
- Cell Biology
- Angiogenesis Research
Background:
- Endostatin is a known endogenous inhibitor of angiogenesis.
- The precise molecular mechanism of endostatin's action and its binding partners remain incompletely understood.
- Endothelial cell surface molecules are implicated in endostatin interactions.
Purpose of the Study:
- To characterize the molecular interactions between endostatin, integrins (alpha5beta1 and alphavbeta3), and heparin/heparan sulfate.
- To elucidate the specific binding sites and affinities involved in these molecular interactions.
- To understand the role of these interactions in the localization of endostatin.
Main Methods:
- Surface plasmon resonance assays were employed to quantify binding kinetics and affinities.
- Site-directed mutagenesis was used to identify crucial residues for binding.
- Molecular modeling was utilized to predict binding interfaces.
Main Results:
- Endostatin forms stable complexes with immobilized alpha5beta1 and alphavbeta3 integrins (KD ≈ 1.8x10⁻⁸ M).
- Arginine residues (Arg27 and Arg139) in endostatin are critical for binding to both integrins and heparin/heparan sulfate.
- Integrins alpha5beta1 and alphavbeta3 directly bind to heparin/heparan sulfate, with alpha5beta1 showing high affinity (KD = 15.5 nM).
- Molecular modeling suggests endostatin binds to the alphavbeta3 integrin headpiece.
Conclusions:
- Endostatin's binding to integrins and heparin/heparan sulfate is mediated by specific arginine residues.
- The distinct binding interactions suggest endostatin does not bind simultaneously to integrins and heparan sulfate.
- Direct integrin-heparin binding may explain the co-localization of endostatin, heparan sulfate, and alpha5beta1 integrin in endothelial cell lipid rafts.
- These findings advance the understanding of endostatin's anti-angiogenic mechanism.
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