Bistable regulation of integrin adhesiveness by a bipolar metal ion cluster.
Integrin alpha(4)beta(7) mediates rolling adhesion in Ca(2+) and Ca(2+) + Mg(2+), and firm adhesion in Mg(2+) and Mn(2+), 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 beta-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 Ca(2+) concentrations, whereas the ADMIDAS mediates the negative regulatory effects of higher Ca(2+) concentrations, which are competed by Mn(2+). The bipolar sites thus stabilize two alternative phases of adhesion.
Chen
JianFeng
J
The CBR Institute of Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Salas
Azucena
A
Springer
Timothy A
TA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020014:K562 Cells; D007962:Leukocytes / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology / Q000502:physiology*; D008345:Manganese / Q000494:pharmacology / Q000502:physiology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013314:Stress, Mechanical; D014162:Transfection
D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; C071777:integrin alpha4beta7; D008345:Manganese; D004533:Egtazic Acid; D008274:Magnesium; D002118:Calcium