Heparin-protein interactions: from affinity and kinetics to biological roles. Application to an interaction network regulating angiogenesis

Matrix Biol. 2014 Apr;35:73-81. doi: 10.1016/j.matbio.2013.11.001. Epub 2013 Nov 16.


Numerous extracellular proteins, growth factors, chemokines, cytokines, enzymes, lipoproteins, involved in a variety of biological processes, interact with heparin and/or heparan sulfate at the cell surface and in the extracellular matrix (ECM). The goal of this study is to investigate the relationship(s) between affinity and kinetics of heparin-protein interactions and the localization of the proteins, their intrinsic disorder and their biological roles. Most proteins bind to heparin with a higher affinity than their fragments and form more stable complexes with heparin than with heparan sulfate. Lipoproteins and matrisome-associated proteins (e.g. growth factors and cytokines) bind to heparin with very high affinity. Matrisome-associated proteins form transient complexes with heparin. However they bind to this glycosaminoglycan with a higher affinity than the proteins of the core matrisome, which contribute to ECM assembly and organization, and than the secreted proteins which are not associated with the ECM. The association rate of proteins with heparin is related to the intrinsic disorder of heparin-binding sites. Enzyme inhibitor activity, protein dimerization, skeletal system development and pathways in cancer are functionally associated with proteins displaying a high or very high affinity for heparin (KD<100 nM). Besides their use in investigating molecular recognition and functions, kinetics and affinity are essential to prioritize interactions in networks and to build network models as discussed for the interaction network established at the surface of endothelial cells by endostatin, a heparin-binding protein regulating angiogenesis.

Keywords: Affinity; Angiogenesis; Heparin–protein interactions; Interaction network; Intrinsic disorder; Kinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cytokines / metabolism
  • Endostatins / metabolism
  • Extracellular Matrix / metabolism*
  • Heparin / metabolism*
  • Heparitin Sulfate / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Kinetics
  • Lipoproteins / metabolism*
  • Macromolecular Substances / metabolism
  • Neoplasms / blood supply*
  • Neovascularization, Pathologic / metabolism*
  • Protein Binding
  • Signal Transduction / physiology


  • Cytokines
  • Endostatins
  • Intercellular Signaling Peptides and Proteins
  • Lipoproteins
  • Macromolecular Substances
  • Heparin
  • Heparitin Sulfate