Crystal structure of human β2-glycoprotein I:implications for phospholipid binding and the antiphospholipid syndrome

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1999
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Schwarzenbacher, Robert
Zeth, Kornelius
Gries, Anna
Kostner, Gerhard M.
Laggner, Peter
Prassl, Ruth
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The high affinity of human plasma β2-glycoprotein I (β2GPI), 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. β2GPI 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 β2GPI 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 β-spiral of four antiparallel β-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 β2GPI 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 β2GPI.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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apolipoprotein H (ApoH), complement control protein, β2-glycoprotein I, short consensus repeat, sushi domain
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ISO 690SCHWARZENBACHER, Robert, Kornelius ZETH, Kay DIEDERICHS, Anna GRIES, Gerhard M. KOSTNER, Peter LAGGNER, Ruth PRASSL, 1999. Crystal structure of human β2-glycoprotein I:implications for phospholipid binding and the antiphospholipid syndrome. In: The EMBO Journal. 1999, 22(22), pp. 6228-6239. ISSN 0261-4189. eISSN 1460-2075. Available under: doi: 10.1093/emboj/18.22.6228
BibTex
@article{Schwarzenbacher1999Cryst-6723,
  year={1999},
  doi={10.1093/emboj/18.22.6228},
  title={Crystal structure of human β2-glycoprotein I:implications for phospholipid binding and the antiphospholipid syndrome},
  number={22},
  volume={22},
  issn={0261-4189},
  journal={The EMBO Journal},
  pages={6228--6239},
  author={Schwarzenbacher, Robert and Zeth, Kornelius and Diederichs, Kay and Gries, Anna and Kostner, Gerhard M. and Laggner, Peter and Prassl, Ruth}
}
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