title: Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies.
abstract: Platelet endothelial cell adhesion molecule 1 (PECAM-1) has many functions, including its roles in leukocyte extravasation as part of the inflammatory response and in the maintenance of vascular integrity through its contribution to endothelial cell-cell adhesion. PECAM-1 has been shown to mediate cell-cell adhesion through homophilic binding events that involve interactions between domain 1 of PECAM-1 molecules on adjacent cells. However, various heterophilic ligands of PECAM-1 have also been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this study. The three-dimensional structure of the extracellular immunoglobulin (Ig) domains of PECAM-1 were constructed using homology modeling and threading methods. Potential heparin/heparan sulfate-binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate-binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein-binding specificity and selectivity. The modeling has predicted two regions in PECAM-1 that appear to bind heparin oligosaccharides. A high-affinity binding site was located in Ig domains 2 and 3, and evidence for a low-affinity site in Ig domains 5 and 6 was obtained. These GAG-binding regions were distinct from regions involved in PECAM-1 homophilic interactions.
authors.affiliation: Western Australian Biomedical Research Institute, Australia.
authors.forename: Neha S
authors.initials: NS
authors.lastname: Gandhi
authors.forename: Deirdre R
authors.initials: DR
authors.lastname: Coombe
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Mancera
mesh_terms: D001665:Binding Sites; D016384:Consensus Sequence; D005110:Extracellular Space / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D007136:Immunoglobulins; D019408:Platelet Endothelial Cell Adhesion Molecule-1