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

Protein S (PS) is a vitamin K-dependent glycoprotein that consists of sever al 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 k inases. Inherited PS deficiency has been associated with thromboembolic dis ease, Yet, study of the mechanisms by which the SI-IBG-like region of PS se rves its essential functions has so far been hampered because of the lack o f structural information. Recently, the three-dimensional (3D) structure of LG domains from plasma SHBG, laminin and neurexin have been reported and w ere found related to the pentraxin family, We used these X-ray structures t o build homology models of the SHBG like region of human PS, We then analyz ed previously reported experimental/clinical data in the light of the predi cted 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 clo se to the interface between the two LG domains and is also surrounded by se gments that have been suggested by synthetic peptide studies to be importan t for C4BP or FVa binding. The 39 point mutations linked to PS deficiencies or reported as neutral variants were rationalized in the 3D structure. (C) 2001 Wiley-Liss, Inc.