ArticleJournal of computer-aided molecular design1997
A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: from biostructural pathology to species-specific cofactor activity.
Article in Journal of computer-aided molecular design, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 37 citations in OpenAlex.
- Ile73Asn mutation in protein C introduces a new N-linked glycosylation site on the first EGF-domain of protein C and causes thrombosis.Haematologica · 2020Article
- C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities.Journal of thrombosis and haemostasis : JTH · 2020Article
- The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex.Journal of thrombosis and haemostasis : JTH · 2019Article
- In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening.Scientific reports · 2017Article
- Gly74Ser mutation in protein C causes thrombosis due to a defect in protein S-dependent anticoagulant function.Thrombosis and haemostasis · 2017Article
- The Journey of Protein S from an Anticoagulant to a Signaling Molecule.JSM biochemistry and molecular biology · 2016Article
- Plasma protein S residues 37-50 mediate its binding to factor Va and inhibition of blood coagulation.Thrombosis and haemostasis · 2013Article
- Phosphorylation of protein S by platelet kinases enhances its activated protein C cofactor activity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
- Down-regulation of the clotting cascade by the protein C pathway.Hematology education. European Hematology Association. Congress. Education Program · 2013Article
- Protein C anticoagulant and cytoprotective pathways.International journal of hematology · 2012Review
- Activated protein C cofactor function of protein S: a critical role for Asp95 in the EGF1-like domain.Blood · 2010Article
- Role of the PROS1 gene in thrombosis: lessons and controversies.Expert review of hematology · 2008Article
- Implication of protein S thrombin-sensitive region with membrane binding via conformational changes in the gamma-carboxyglutamic acid-rich domain.The Biochemical journal · 2001Article
- Screening the molecular surface of human anticoagulant protein C: a search for interaction sites.Journal of computer-aided molecular design · 2001Article
- Chemical synthesis and spontaneous folding of a multidomain protein: anticoagulant microprotein S.Proceedings of the National Academy of Sciences of the United States of America · 2000Article
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Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its gamma-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS 'faces' involving regions of residues Arg49-Gln52-Lys97 (TSR-EGF-1) and Thr103-Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.
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