Mucosal addressin cell adhesion molecule-1: a structural and functional analysis demarcates the integrin binding motif
| Autor: | J L Viney, S Jones, H H Chiu, B Lagrimas, M E Renz, L G Presta, D Jackson, K J Hillan, S Lew, S Fong |
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| Rok vydání: | 1996 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 157:2488-2497 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.157.6.2488 |
| Popis: | The leukocyte integrin receptor, alpha 4 beta 7, and the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) are postulated to be important in regulating lymphocyte trafficking to normal intestine. Here we provide the first description of MAdCAM-1 expression in inflamed intestine. Using mouse models of experimentally induced colitis, we show a concordant increase in MAdCAM-1 expression associated with increased cellular infiltrates in areas of intestinal inflammation. To understand more of the molecular nature of the interactions between MAdCAM-1 and its leukocyte ligand, the alpha 4 beta 7 integrin receptor, we have analyzed the structural and functional properties of chimeric recombinant MAdCAM-1 proteins in vitro. Using site-directed mutagenesis and molecular modeling, we demarcate the alpha 4 beta 7 binding motif as three linear residues within the C-D loop in the first domain of MAdCAM-1. Mutation of residue L40, D41, or T42 in the first domain completely abrogates alpha 4 beta 7+ cell binding and cellular activation. Mutagenesis of other residues in the first domain do not impact these functions. We have modeled peptides based on the predicted structure of the alpha 4 beta 7 integrin binding motif on MAdCAM-1 and are able to show specific and selective blocking of cell binding. These observations suggest that the amino acid residues LDT on MAdCAM-1 play a role in the interaction with alpha 4 beta 7 in cell adherence and cell activation. |
| Databáze: | OpenAIRE |
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