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4ß1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes1
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kindgom
The leukocyte integrin 
4ß1 is a
receptor for both cell surface ligands (VCAM-1 and mucosal addressin
cell adhesion molecule-1 (MAdCAM-1)) and extracellular matrix
components (fibronectin). Through regulated interactions with these
molecules, 4ß1 mediates leukocyte
migration from the vasculature at sites of inflammation. Regulation of
integrin activity plays a key role in controlling leukocyte-adhesive
events and appears to be partly determined by changes in integrin
conformation. Several mAbs that recognize ligand-induced binding site
epitopes on integrins have been characterized, and a subset of these
mAbs are capable of stimulating integrin-ligand binding. Conversely,
some mAbs recognize epitopes that are attenuated by ligand engagement
and allosterically inhibit ligand binding. To gain insight into
ligand-specific effects on integrin conformation, we have examined the
ability of different ligands to modulate the binding of four distinct
classes (A, B1, B2, and C) of anti-4 Abs to
4ß1. VCAM-1 attenuated B (antifunctional)
class epitopes via an allosteric mechanism and also allosterically
inhibited the binding of the function-blocking
anti-ß1 mAb 13. Additional
4ß1 ligands (fibronectin fragments,
MAdCAM-1, and the CS1 peptide) also inhibited mAb 13-integrin binding;
however, the epitopes of the class B anti-4 mAbs
were attenuated by the fibronectin fragments, but not by MAdCAM-1 or
the CS1 peptide. Of the two anti-4 class A mAbs
examined, one recognized an epitope that was induced uniquely by
VCAM-1. Taken together, these data suggest that overlapping but
distinct binding mechanisms exist for different
4ß1 ligands and that distinct
conformational changes are induced upon integrin engagement by
different ligands.
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