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Structural basis of membrane binding by Gla domains of vitamin K–dependent proteins

Nature Structural & Molecular Biology volume 10, pages 751–756 (2003)Cite this article

Abstract

In a calcium-dependent interaction critical for blood coagulation, vitamin K–dependent blood coagulation proteins bind cell membranes containing phosphatidylserine via γ-carboxyglutamic acid–rich (Gla) domains. Gla domain–mediated protein-membrane interaction is required for generation of thrombin, the terminal enzyme in the coagulation cascade, on a physiologic time scale. We determined by X-ray crystallography and NMR spectroscopy the lysophosphatidylserine-binding site in the bovine prothrombin Gla domain. The serine head group binds Gla domain–bound calcium ions and Gla residues 17 and 21, fixed elements of the Gla domain fold, predicting the structural basis for phosphatidylserine specificity among Gla domains. Gla domains provide a unique mechanism for protein-phospholipid membrane interaction. Increasingly Gla domains are being identified in proteins unrelated to blood coagulation. Thus, this membrane-binding mechanism may be important in other physiologic processes.

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Figure 1: Structure of the PT1–Ca2+– lysophosphatidylserine complex.
Figure 2: Bonding network for binding of lysophosphatidylserine with Ca2+-liganded PT1.
Figure 3: Comparison of the solution and crystal structures of prothrombin Gla domains.
Figure 4: Model of PT1 interacting with a phospholipid bilayer.

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Acknowledgements

We thank Brookhaven National Laboratories for time on beamlines X12C, X8C and X25 and J. Wang for assistance with collection of X-ray data. This work was supported by grants from the US National Institutes of Health to B.C.F., B.S., B.F. and M.A.G. and from the American Heart Association to A.C.R.

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  1. Mingdong Huang and Alan C Rigby: These two authors contributed equally to this article.

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center and Department of Medicine, Center for Hemostasis and Thrombosis Research, Harvard Medical School, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Mingdong Huang, Alan C Rigby, Xavier Morelli, Marianne A Grant, Guiqing Huang, Bruce Furie & Barbara C Furie

  2. Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, 02118, Massachusetts, USA

    Barbara Seaton

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  1. Mingdong Huang
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Correspondence to Barbara C Furie.

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Huang, M., Rigby, A., Morelli, X. et al. Structural basis of membrane binding by Gla domains of vitamin K–dependent proteins. Nat Struct Mol Biol 10, 751–756 (2003). https://doi.org/10.1038/nsb971

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