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Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation

Nature Structural Biology volume 9, pages 282–287 (2002)Cite this article

Abstract

Cysteine-rich repeats in the integrin β subunit stalk region relay activation signals to the ligand-binding headpiece. The NMR solution structure and disulfide bond connectivity of Cys-rich module-3 of the integrin β2 subunit reveal a nosecone-shaped variant of the EGF fold, termed an integrin-EGF (I-EGF) domain. Interdomain contacts between I-EGF domains 2 and 3 observed by NMR support a model in which the modules are related by an approximate two-fold screw axis in an extended arrangement. Our findings complement a 3.1 Å crystal structure of the extracellular portion of integrin αVβ3, which lacks an atomic model for I-EGF2 and a portion of I-EGF3. The disulfide connectivity of I-EGF3 chemically assigned here differs from the pairings suggested in the αVβ3 structure. Epitopes that become exposed upon integrin activation and residues that restrain activation are defined in β2 I-EGF domains 2 and 3. Superposition on the αVβ3 structure reveals that they are buried. This observation suggests that the highly bent αVβ3 structure represents the inactive conformation and that release of contacts with I-EGF modules 2 and 3 triggers a switchblade-like opening motion extending the integrin into its active conformation.

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Figure 1: Integrin domain organization and the Cys-rich repeats.
Figure 2: Solution structure of I-EGF3.
Figure 3: Interdomain interactions between I-EGF2 and I-EGF3.
Figure 4: Integrin activation.

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Acknowledgements

Supported by grants from the NIH, Pew Charitable Trust and the American Heart Association.

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Author notes

  1. Natalia Beglova, Stephen C. Blacklow, Junichi Takagi and Timothy A. Springer: Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, Masschusetts 02115, USA. These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, 75 Francis St., Boston, 02115, Masschusetts, USA

    Natalia Beglova, Stephen C. Blacklow, Junichi Takagi & Timothy A. Springer

  2. The Center for Blood Research, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Junichi Takagi & Timothy A. Springer

Authors
  1. Natalia Beglova
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  2. Stephen C. Blacklow
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  3. Junichi Takagi
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  4. Timothy A. Springer
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Correspondence to Stephen C. Blacklow or Timothy A. Springer.

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Beglova, N., Blacklow, S., Takagi, J. et al. Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation. Nat Struct Mol Biol 9, 282–287 (2002). https://doi.org/10.1038/nsb779

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