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

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 SHBG-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. Proteins 2001;43:203-216.

Functional properties of the sex‐hormone‐binding globulin (SHBG)‐like domain of the anticoagulant protein S

“…This is in keeping with the recently solved crystal structure of plasma SHBG [14] and of the LG4‐LG5 domains of laminin α‐chain [13], showing the presence of two different types of Ca 2+ ‐binding site on LG‐domains. It is also consistent with a three‐dimensional model of the SHBG‐like domain of PS [31], revealing the presence of a potential Ca 2+ ‐binding site in the first LG‐domain of PS; no Ca 2+ binding site was clearly identified in the second LG‐domain.…”

“…A second point that requires clarification is the binding of Ca 2+ . Indeed, results of functional studies with chimeric proteins [24,25], as well as three‐dimensional computer modeling of the SHBG‐like domain [31], strongly argue for the presence of a Ca 2+ ‐binding site within the SHBG‐like domain, but this binding has never been directly demonstrated, as the EGF domains, and particularly the adjacent EGF4 domain, may support Ca 2+ binding too [32,33].…”

Vitamin K–Dependent Protein S: Beyond the Protein C Pathway

“…[45][46][47][48][49][50] The SHBG-like region is additionally found to be important for the synergistic APC-cofactor activity with FV in the degradation of FVIIIa in the Xase complex. 13,51,52 APC-Independent Anticoagulant Activity of Protein S…”

Fulminant bilateral cerebral infarction caused by paradoxical embolism in a patient with protein S Ala525Val substitution

“…Inherited PC and PS deficiencies are more common in Japan than in Western countries. Many point mutations resulting in PC or PS deficiency have been reported to date . We report a patient with fulminant cerebral infarction in the bilateral middle cerebral artery (MCA) territories, caused by paradoxical embolism.…”

“…Thrombin is the final protease in the blood coagulation cascade, and interacts with antithrombin to form the thrombin–antithrombin complex, which converts PC to activated PC (APC). APC inactivates the activated coagulation factors, Va and VIIIa . This important negative feedback mechanism prevents excessive blood coagulation.…”