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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Bruno O. Villoutreix
  • Björn Dahlbäck
  • Delphine Borgel
  • Sophie Gandrille
  • Yves A. Muller
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry

Keywords

  • protein modeling, blood coagulation, thrombosis
Original languageEnglish
Pages (from-to)203-216
JournalProteins
Volume43
Issue number2
Publication statusPublished - 2001
Publication categoryResearch
Peer-reviewedYes