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Bistable regulation of integrin adhesiveness by a bipolar metal ion cluster

Nature Structural & Molecular Biology volume 10, pages 995–1001 (2003)Cite this article

Abstract

Integrin α4β7 mediates rolling adhesion in Ca2+ and Ca2+ + Mg2+, and firm adhesion in Mg2+ and Mn2+, mimicking the two key steps in leukocyte accumulation in inflamed vasculature. We mutated an interlinked linear array of three divalent cation-binding sites present in integrin β-subunit I-like domains. The middle, metal ion–dependent adhesion site (MIDAS) is required for both rolling and firm adhesion. One polar site, that adjacent to MIDAS (ADMIDAS), is required for rolling because its mutation results in firm adhesion. The other polar site, the ligand-induced metal binding site (LIMBS), is required for firm adhesion because its mutation results in rolling. The LIMBS mediates the positive regulatory effects of low Ca2+ concentrations, whereas the ADMIDAS mediates the negative regulatory effects of higher Ca2+ concentrations, which are competed by Mn2+. The bipolar sites thus stabilize two alternative phases of adhesion.

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Figure 1: The β-subunit I-like domain metal-binding sites and regulation of α4β7 adhesive modality by divalent cations.
Figure 2: Effect of the metal ion–binding site mutations on the adhesive modality of α4β7 and resistance to detachment in shear flow.
Figure 3: Resistance to detachment.
Figure 4: Positive and negative regulation of α4β7 by Ca2+ and competition between Ca2+ and Mn2+.

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Acknowledgements

We thank D.J. Erle and M.J. Briskin for providing wild-type human integrin β7 cDNA and α4β7 K562 stable transfectant and human MAdCAM-1/Fc, respectively. This work was supported by a grant from the US National Institutes of Health.

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  1. The CBR Institute of Biomedical Research and Department of Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    JianFeng Chen, Azucena Salas & Timothy A Springer

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Correspondence to Timothy A Springer.

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Chen, J., Salas, A. & Springer, T. Bistable regulation of integrin adhesiveness by a bipolar metal ion cluster. Nat Struct Mol Biol 10, 995–1001 (2003). https://doi.org/10.1038/nsb1011

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