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Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

Nature volume 432, pages 59–67 (2004)Cite this article

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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Figure 1: Quaternary rearrangements in the integrin ectodomain.
Figure 2: Structure of the αIIbβ3 headpiece.
Figure 3: The binding sites for ligand-mimetic antagonists and fibrinogen at the α/β subunit interface.
Figure 4: Allostery in the β I domain and comparison with α I domain.
Figure 5: The hybrid and PSI domains and their interfaces.

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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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  1. Junichi Takagi

    Present address: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

Authors and Affiliations

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

    Tsan Xiao, Junichi Takagi & Timothy A. Springer

  2. Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Barry S. Coller

  3. Dana-Farber Cancer Institute, Departments of Pediatrics, Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Massachusetts, 02115, Boston, USA

    Jia-Huai Wang

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Correspondence to Timothy A. Springer.

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Competing interests

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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