title: LPAM-1 (integrin alpha 4 beta 7)-ligand binding: overlapping binding sites recognizing VCAM-1, MAdCAM-1 and CS-1 are blocked by fibrinogen, a fibronectin-like polymer and RGD-like cyclic peptides.
abstract: The alpha 4 integrin LPAM-1 (alpha 4 beta 7) mediates lymphocyte attachment within the extracellular matrix (ECM) by adhering to the connecting segment (CS)-1 site of fibronectin (FN). Here we reveal that very late antigen (VLA)-4 LPAM-1+ T cell lymphoma TK-1 cells bind via LPAM-1 to multiple copies of the RGD sequence engineered within an FN-like polymer. Further, the small conformationally restrained RGD-like cyclic peptides 1-adamantaneacetyl-Cys-Gly-Arg-Gly-Asp-Ser-Pro-Cys and Arg-Cys-Asp-thioproline-Cys inhibit the adhesion of TK-1 cells to immobilized CS-1 peptide, and to endothelial counterreceptors for LPAM-1, namely mucosal addressin cell adhesion molecule (MAdCAM)-1 and vascular cell adhesion molecule (VCAM)-1. Spontaneous adhesion of the VLA-4- LPAM-1+ B lymphoma cell line RPMI 8866 to CS-1 was likewise inhibited, confirming a previously undocumented ability of LPAM-1 to recognize the RGD tripeptide. The RGD-binding site in LPAM-1 either overlaps or is identical to sites required for interaction with MAdCAM-1, VCAM-1, and the CS-1. The binding of LPAM-1 and VLA-4 to RGD-containing ligands may have relevance in vivo given that fibrinogen at physiological concentrations is able to partially block the binding of TK-1 cells to MAdCAM-1. Hence fibrinogen and other vascular RGD-containing proteins may have mild anti-inflammatory activity required for maintaining effective homeostasis, analogous to the anti-thrombogenic activity of the vascular endothelium.
authors.affiliation: Department of Molecular Medicine, School of Medicine, University of Auckland, New Zealand.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: P M
authors.initials: PM
authors.lastname: Cardarelli
authors.forename: K
authors.initials: K
authors.lastname: Lehnert
authors.forename: S
authors.initials: S
authors.lastname: Rowland
authors.forename: G W
authors.initials: GW
authors.lastname: Krissansen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism; D011485:Protein Binding; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019010:Vascular Cell Adhesion Molecule-1; C094697:glutamyl-isoleucyl-leucyl-aspartyl-valine; C071777:integrin alpha4beta7; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen