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Three-dimensional model of the SHBG-like region of anticoagulant protein S: New structure-function insights

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Author

  • Bruno O. Villoutreix
  • Björn Dahlbäck
  • Delphine Borgel
  • Sophie Gandrille
  • Yves A. Muller

Summary, in English

Protein S (PS) is a vitamin K-dependent glycoprotein that consists of several modules including a C-terminal sex hormone-binding globulin (SHBG)-like domain that has been subdivided into two laminin LG-type domains, The SHBG-like region of PS is known to bind to a complement regulator molecule, C4b-binding protein (C4BP), coagulation factor Va (FVa) and receptor tyrosine kinases. Inherited PS deficiency has been associated with thromboembolic disease, Yet, study of the mechanisms by which the SI-IBG-like region of PS serves its essential functions has so far been hampered because of the lack of structural information. Recently, the three-dimensional (3D) structure of LG domains from plasma SHBG, laminin and neurexin have been reported and were found related to the pentraxin family, We used these X-ray structures to build homology models of the SHBG like region of human PS, We then analyzed previously reported experimental/clinical data in the light of the predicted structures. A potential calcium-binding site is found in the first LG domain of PS and D292 could play a role in this process, This region is close to the interface between the two LG domains and is also surrounded by segments that have been suggested by synthetic peptide studies to be important for C4BP or FVa binding. The 39 point mutations linked to PS deficiencies or reported as neutral variants were rationalized in the 3D structure.

Publishing year

2001

Language

English

Pages

203-216

Publication/Series

Proteins

Volume

43

Issue

2

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Medicinal Chemistry

Keywords

  • protein modeling
  • blood coagulation
  • thrombosis

Status

Published

Research group

  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 0887-3585