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Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13062-7. Epub 2006 Aug 18.

Regulation of outside-in signaling and affinity by the beta2 I domain of integrin alphaLbeta2.

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  • 1CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.


The adhesiveness of integrin alpha(L)beta(2) is modulated by divalent cations. We mutated three metal ion-binding sites in the beta(2) I domain. The metal ion-dependent adhesion site (MIDAS) and the ligand-induced metal-binding site are required for ligand binding and sufficient for synergism between Ca(2+) and Mg(2+). Adjacent to MIDAS (ADMIDAS) mutants are constitutively active but remain bent, with poor exposure of a beta(2) stalk region epitope. Fluorescence resonance energy transfer between fluorescent protein-fused alpha(L) and beta(2) cytoplasmic domains showed that ADMIDAS mutation abrogated ligand binding-induced spatial separation of cytoplasmic domains. Furthermore, ADMIDAS mutation abolished spreading on ligand-bearing substrates. Thus, beta(2) I domain metal ion-binding sites regulate alpha(L) I domain affinity, and the ADMIDAS is required for outside-in signaling.

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