DOI: 10.4049/jimmunol.160.9.4508. Analysis of Ligand-Induced and Ligand-Attenuated Epitopes on the Leukocyte Integrin α4β1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes

Analysis of Ligand-Induced and Ligand-Attenuated Epitopes on the Leukocyte Integrin α4β1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes

10.4049/jimmunol.160.9.4508

Crossref journal-article

Oxford University Press (OUP)

The Journal of Immunology (286)

Abstract

AbstractThe leukocyte integrin α4β1 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, α4β1 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-α4 Abs to α4β1. VCAM-1 attenuated B (antifunctional) class epitopes via an allosteric mechanism and also allosterically inhibited the binding of the function-blocking anti-β1 mAb 13. Additional α4β1 ligands (fibronectin fragments, MAdCAM-1, and the CS1 peptide) also inhibited mAb 13-integrin binding; however, the epitopes of the class B anti-α4 mAbs were attenuated by the fibronectin fragments, but not by MAdCAM-1 or the CS1 peptide. Of the two anti-α4 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 α4β1 ligands and that distinct conformational changes are induced upon integrin engagement by different ligands.

Bibliography

Newham, P., Craig, S. E., Clark, K., Mould, A. P., & Humphries, M. J. (1998). Analysis of Ligand-Induced and Ligand-Attenuated Epitopes on the Leukocyte Integrin Î±4Î²1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes. The Journal of Immunology, 160(9), 4508â4517.

Authors 5

Peter Newham (first)
Sue E. Craig (additional)
Katherine Clark (additional)
A. Paul Mould (additional)
Martin J. Humphries (additional)

References 50 Referenced 35

Dates

Type	When
Created	2 years, 8 months ago (Dec. 31, 2022, 7:02 p.m.)
Deposited	8 months ago (Jan. 2, 2025, 1:01 p.m.)
Indexed	5 months, 1 week ago (March 29, 2025, 1:05 p.m.)
Issued	27 years, 4 months ago (May 1, 1998)
Published	27 years, 4 months ago (May 1, 1998)
Published Print	27 years, 4 months ago (May 1, 1998)

Funders 0

None

BibTeX

@article{Newham_1998, title={Analysis of Ligand-Induced and Ligand-Attenuated Epitopes on the Leukocyte Integrin α4β1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes}, volume={160}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.160.9.4508}, DOI={10.4049/jimmunol.160.9.4508}, number={9}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Newham, Peter and Craig, Sue E. and Clark, Katherine and Mould, A. Paul and Humphries, Martin J.}, year={1998}, month=may, pages={4508–4517} }

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