Swing-out of the β3 hybrid domain is required for αIIbβ3 priming and normal cytoskeletal reorganization, but not adhesion to immobilized fibrinogen

PloS One
Ming ChengB S Coller

Abstract

Structural and functional analyses of integrin αIIbβ3 has implicated swing-out motion of the β3 hybrid domain in αIIbβ3 activation and ligand binding. Using data from targeted molecular dynamics (TMD) simulations, we engineered two disulfide-bonded mutant receptors designed to limit swing-out (XS-O). XS-O mutants cannot bind the high Mr ligand fibrinogen in the presence of an activating mAb or after introducing mutations into the αIIb subunit designed to simulate inside-out signaling. They also have reduced capacity to be "primed" to bind fibrinogen by pretreatment with eptifibatide. They can, however, bind the small RGD venom protein kistrin. Despite their inability to bind soluble fibrinogen, the XS-O mutants can support adhesion to immobilized fibrinogen, although such adhesion does not initiate outside-in signaling leading to normal cytoskeletal reorganization. Collectively, our data further define the biologic role of β3 hybrid domain swing-out in both soluble and immobilized high Mr ligand binding, as well as in priming and outside-in signaling. We also infer that swing-out is likely to be a downstream effect of receptor extension.

References

May 3, 1991·Cell·D R PhillipsR M Scarborough
Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·M S DennisR A Lazarus
Sep 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·D A Cheresh
Mar 1, 1994·The Journal of Cell Biology·T E O'TooleM H Ginsberg
Mar 22, 1996·The Journal of Biological Chemistry·P E HughesM H Ginsberg
Feb 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Bing-Hao LuoJunichi Takagi
Dec 19, 2003·The Journal of Biological Chemistry·Bing-Hao LuoTimothy A Springer
Jan 20, 2004·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·D P ChewE J Topol
May 12, 2004·Current Pharmaceutical Design·Dermot Cox
Jun 19, 2004·Blood·Sanford J Shattil, Peter J Newman
Jan 5, 2007·Annual Review of Immunology·Bing-Hao LuoTimothy A Springer
Jul 23, 2008·Perspectives in Vascular Surgery and Endovascular Therapy·Kimon Bekelis, Nicos Labropoulos
Jan 6, 2010·The Journal of Cell Biology·Feng YeMark H Ginsberg
Apr 7, 2010·The Journal of Biological Chemistry·Robert BlueBarry S Coller
Jul 31, 2010·The Journal of Biological Chemistry·Benoit J SmaggheTimothy A Springer
Oct 5, 2010·The Journal of Biological Chemistry·Tetsuji KamataSadakazu Aiso
Nov 13, 2010·Arteriosclerosis, Thrombosis, and Vascular Biology·Zhenyu LiXiaoping Du
Mar 23, 2011·Cold Spring Harbor Perspectives in Biology·Iain D Campbell, Martin J Humphries
Jul 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Antreas C KalliMark S P Sansom

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Citations

Mar 15, 2014·Current Opinion in Hematology·Edward F PlowTatiana V Byzova
Sep 29, 2017·Molecular Biology of the Cell·Yunfeng ChenCheng Zhu
Apr 2, 2016·The Journal of Biological Chemistry·Akio OzawaKiyotoshi Sekiguchi

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Methods Mentioned

BETA
glycosylation
transfection
immunoprecipitation
flow cytometry
immunoprecipitations

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