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  • The EMBO Journal (1999) 18, 6228 - 6239
  • doi:10.1093/emboj/18.22.6228

Crystal structure of human bold beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome

Robert Schwarzenbacher1, Kornelius Zeth2, Kay Diederichs3, Anna Gries4, Gerhard M. Kostner5, Peter Laggner1 and Ruth Prassl1

  1. Institute of Biophysics and X-ray Structure Research, Austrian Academy of Sciences, Steyrergasse 17/6, A-8020 Graz, Austria
  2. MPI for Biochemistry, Department of Molecular Structural Biology, Am Klopferspitz 18a, D-82152 Martinsried, Germany
  3. Faculty of Biology, University of Konstanz, POB-55 60, D-78457 Konstanz, Germany
  4. Institute of Physiology, A-8010 Graz, Austria
  5. Institute of Medical Biochemistry, University of Graz, Harrachgasse 21, A-8010 Graz, Austria

Correspondence to:

Ruth Prassl, E-mail: ruth.prassl@oeaw.ac.at

Received 9 August 1999; Accepted 21 September 1999; Revised 21 September 1999

The high affinity of human plasma beta2-glycoprotein I (beta2GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. beta2GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the beta2GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans. The structure reveals four complement control protein modules and a distinctly folding fifth C-terminal domain arranged like beads on a string to form an elongated J-shaped molecule. Domain V folds into a central beta-spiral of four antiparallel beta-sheets with two small helices and an extended C-terminal loop region. It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313–316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances. The beta2GPI structure reveals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid-binding capacity of beta2GPI.

  • Keywords:

    • apolipoprotein H (ApoH),
    • complement control protein,
    • beta2-glycoprotein I,
    • short consensus repeat,
    • sushi domain