Abstract
Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin α and β subunits form a head and two long legs in the ectodomain and span the membrane. Here, we define with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin αIIbβ3. Allostery in the β3 I domain alters three metal binding sites, associated loops and α1- and α7-helices. Piston-like displacement of the α7-helix causes a 62° reorientation between the β3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper β3 leg causes a 70 Å separation between the knees of the α and β legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.
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Acknowledgements
We thank colleagues in the Springer laboratory for supporting data and stimulating discussions, B. Kessler for tandem mass spectrometry, E. Yvonne Jones at Oxford for sema4D coordinates, members of the J.H.W. and M. Eck laboratories and the staff at APS and CHESS for assistance with crystallography, M. Gerstein and N. Echols (Yale University) for the morphing script used in producing movies, and Y. Cheng for help with comparing crystal structures and the electron microscopy map. Supported by NIH grants to T.A.S., J.H.W. and B.S.C.
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T.A.S. owns shares in Millennium Pharmaceuticals, which markets eptifibatide.
B.S.C. is an inventor of abciximab, an αIIbβ3 antagonist, and in accord with Federal law and the policies of the Research Foundation of the State University
of New York, shares in royalties paid to the Foundation. The rest of the authors declare that they have no competing financial interests.
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Xiao, T., Takagi, J., Coller, B. et al. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432, 59–67 (2004). https://doi.org/10.1038/nature02976
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DOI: https://doi.org/10.1038/nature02976
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