A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: From biostructural pathology to specie

摘要: Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is mosaic that interacts with the phospholipid membrane via its gamma-carboxyglutamate-rich (Gla) module. This module followed by thrombin-sensitive region (TSR), sensitive thrombin cleavage, four epidermal growth factor (EGF)-like modules and last referred sex hormone binding globulin (SHBG) domain. Of these, TSR first EGF-like regions have been shown be important for interaction APC. Difficulties in crystallising PS so far hindered study at atomic level. Here, we report theoretical models Gla EGF-1 of human constructed using prothrombin X experimental structures. The was built interactively. Analysis model linked large body biochemical literature on related proteins leads suggestions (i) stabilises calcium-loaded through hydrophobic ionic interactions conformation depends presence module; (ii) does not form calcium site but protected from cleavage owing short secondary structure elements close contact (iii) missense mutations this are consistent structural data, except one case needs further investigation; (iv) two 'faces' involving residues Arg49-Gln52-Lys97 (TSR-EGF-1) Thr103-Pro106 (EGF-1) may involved APC they richer nonconservative substitution when comparing bovine S. preliminary helps plan future experiments resulting data will used validate optimise present structure.