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Paul A Mould – One of the best experts on this subject based on the ideXlab platform.

  • distinct roles of β1 metal ion dependent Adhesion Site midas adjacent to midas admidas and ligand associated metal binding Site limbs cation binding Sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould

    Abstract:

    Abstract Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding Sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding Sites: the metal-ion dependent Adhesion Site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding Site). The role of these Sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+, and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent Site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding Site, occupancy of which increases the affinity of Mg2+ for the MIDAS.

  • distinct roles of β1 metal ion dependent Adhesion Site midas adjacent to midas admidas and ligand associated metal binding Site limbs cation binding Sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould

    Abstract:

    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding Sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding Sites: the metal-ion dependent Adhesion Site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding Site). The role of these Sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent Site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding Site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

Robert C. Liddington – One of the best experts on this subject based on the ideXlab platform.

  • cellular activation of leukocyte function associated antigen 1 and its affinity are regulated at the i domain allosteric Site
    Journal of Immunology, 2001
    Co-Authors: Mark L Lupher, Robert C. Liddington, Edith A S Harris, Chan R Beals, Liming Sui, Donald E Staunton

    Abstract:

    The I domain of the integrin LFA-1 possesses a ligand binding interface that includes the metal ion-dependent Adhesion Site. Binding of the LFA-1 ligand, ICAM-1 to the metal ion-dependent Adhesion Site is regulated by the I domain allosteric Site (IDAS). We demonstrate here that intracellular signaling leading to activation of LFA-1 binding to ICAM-1 is regulated at the IDAS. Inhibitory mutations in or proximal to the IDAS are dominant to cytoplasmic signals that activate binding to ICAM-1. In addition, mutational activation at the IDAS greatly increases the binding of lymphocyte-expressed LFA-1 to ICAM-1 in response to PMA, but does not result in constitutive binding. Binding of a novel CD18 activation epitope mAb to LFA-1 in response to soluble ICAM-1 binding was also blocked by inhibitory and was enhanced by activating IDAS mutations. Surface plasmon resonance using soluble wild-type LFA-1 and an IDAS mutant of LFA-1 indicate that the IDAS can regulate a 6-fold change in the K(d) of ICAM-1 binding. The K(d) of wild-type LFA-1 (1.2 x 10(-1) s(-1)) differed with that of the activating IDAS mutant (1.9 x 10(-2) s(-1)), but their K(a) values were identical (2.2 x 10(5) M(-1)s(-1)). We propose that IDAS regulates the binding of LFA-1 to ICAM-1 activated by intracellular signals. IDAS can control the affinity state of LFA-1 with concomitant I domain and CD18 conformational changes.

  • interaction between collagen and the α2 i domain of integrin αβ1 critical role of conserved residues in the metal ion dependent Adhesion Site midas region
    Journal of Biological Chemistry, 1999
    Co-Authors: Tetsuji Kamata, Robert C. Liddington, Yoshikazu Takada

    Abstract:

    Abstract A docking model of the α2 I-domain and collagen has been proposed based on their crystal structures (Emsley, J., King, S., Bergelson, J., and Liddington, R. C. (1997) J. Biol. Chem. 272, 28512–28517). In this model, several amino acid residues in the I-domain make direct contact with collagen (Asn-154, Asp-219, Leu-220, Glu-256, His-258, Tyr-285, Asn-289, Leu-291, Asn-295, and Lys-298), and the protruding C-helix of α2 (residues 284–288) determines ligand specificity. Because most of the proposed critical residues are not conserved, different I-domains are predicted to bind to collagen differently. We found that deleting the entire C-helix or mutating the predicted critical residues had no effect on collagen binding to whole α2β1, with the exception that mutating Asn-154, Asp-219, and His-258 had a moderate effect. We performed further studies and found that mutating the conserved surface-exposed residues in the metal ion-dependent Adhesion Site (MIDAS) (Tyr-157 and Gln-215) significantly blocks collagen binding. We have revised the docking model based on the mutagenesis data. In the revised model, conserved Tyr-157 makes contact with collagen in addition to the previously proposed Asn-154, Asp-219, His-258, and Tyr-285 residues. These results suggest that the collagen-binding I-domains (e.g. α1, α2, and α10) bind to collagen in a similar fashion.

  • Echovirus 1 interaction with the human very late antigen-2 (integrin α2β1) I domain: Identification of two independent virus contact Sites distinct from the metal ion-dependent Adhesion Site
    The Journal of biological chemistry, 1997
    Co-Authors: Sandra L. King, Tetsuji Kamata, Jennifer A. Cunningham, Jonas Emsley, Robert C. Liddington, Yoshikazu Takada, Jeffrey M. Bergelson

    Abstract:

    Abstract The human integrin very late antigen (VLA)-2 (CD49b/CD29) mediates interactions with collagen and is the receptor for echovirus 1. Binding Sites for both collagen and echovirus 1 have been mapped to the I domain within the α2 subunit of the VLA-2 α2β1 heterodimer. Although murine VLA-2 interacts with collagen, it does not bind virus. We have used isolated human-murine chimeric I domains expressed as glutathione S-transferase fusion proteins in Escherichia coli to identify two groups of amino acids, 199–201 and 212–216, independently involved in virus attachment. These residues are distinct from the metal ion-dependent Adhesion Site previously demonstrated to be essential for VLA-2 interactions with collagen. Mutations in three metal ion-dependent Adhesion Site residues that abolish Adhesion to collagen had no effect on virus binding. These results confirm that different Sites within the I domain are responsible for VLA-2 interaction with extracellular matrix proteins and with viral ligands.

Martin J Humphries – One of the best experts on this subject based on the ideXlab platform.

  • distinct roles of β1 metal ion dependent Adhesion Site midas adjacent to midas admidas and ligand associated metal binding Site limbs cation binding Sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould

    Abstract:

    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding Sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding Sites: the metal-ion dependent Adhesion Site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding Site). The role of these Sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent Site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding Site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

  • distinct roles of β1 metal ion dependent Adhesion Site midas adjacent to midas admidas and ligand associated metal binding Site limbs cation binding Sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould

    Abstract:

    Abstract Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding Sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding Sites: the metal-ion dependent Adhesion Site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding Site). The role of these Sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+, and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent Site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding Site, occupancy of which increases the affinity of Mg2+ for the MIDAS.

  • Bamacan BM-CSPG
    The Extracellular Matrix FactsBook, 1998
    Co-Authors: Shirley Ayad, Martin J Humphries, Ray Boot-handford, Karl E. Kadler, Adrian Shuttleworth

    Abstract:

    The chapter discusses the structural and functional Sites of bamacan. Bamacan is a chondroitin sulfate proteoglycan distinct from perlecan and agrin and present in a number of basement membranes. The protein’s structural features are in common with proteins that stabilize the chromosomal scaffold at mitosis. As deduced from complementary DNA (cDNA) sequences, the protein’s predicted molecular weight is 138,000. The predicted protein is divided into five domains. The first domain—165 amino acids—lack cysteine and are hydrophilic. Domains II and IV contain 335 and 364 amino acids, respectively, and have high potentials for coiled-coil structure. Domain III lies between two coiled-coil regions and is comprised of 165 amino acids. It contains four cysteines and a potential cell Adhesion Site. The chapter also presents the primary structure and isolation methods of bamacan.