Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Viney, J.L. et al.

Mucosal addressin cell adhesion molecule-1: a structural and functional analysis demarcates the integrin binding motif.

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.[1]

References

Mucosal addressin cell adhesion molecule-1: a structural and functional analysis demarcates the integrin binding motif. Viney, J.L., Jones, S., Chiu, H.H., Lagrimas, B., Renz, M.E., Presta, L.G., Jackson, D., Hillan, K.J., Lew, S., Fong, S. J. Immunol. (1996) [Pubmed]

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