SHBG REGION OF THE ANTICOAGULANT COFACTOR PROTEIN-S - SECONDARY STRUCTURE PREDICTION, CIRCULAR-DICHROISM SPECTROSCOPY, AND ANALYSIS OF NATURALLY-OCCURRING MUTATIONS

Protein S (PS) and growth arrest specific factor 6 (GAS6) are vitamin K-dependent proteins with similar structures, They are mosaic proteins possessing a carboxyl-terminal region presenting sequence similarity with plasma sex hormone binding globulin (plasma SHBG), although appar ently not involved in steroid binding, The SHBG-like modules have sequ ence similarity with the G repeats of the chain A of laminin, Laminin G repeats have been reported to contain mainly beta-strands (about 40- 50%) but no or little alpha structure by circular dichroism (CD) spect roscopy, Secondary structure predictions carried out in the present wo rk unexpectedly showed a 20 to 27% helices content in the SHBG region of PS/GAS6 (about 100 residues), while plasma SHBG and laminin G repea ts had around 10% helices, CD measurements for human PS indicated also that its SHBG region had about 100 residues in alpha-helical structur e, These data suggest that the SHBG region of PS/GAS6 on the one hand, and the laminin G repeats and possibly plasma SHBG on the other hand, could present important structural differences, Previously reported p olymorphisms and point mutations leading to PS deficiency and thrombop hilia have been analyzed with our structural predictions, We found a g ood agreement between these structural predictions, CD measurements, e xperimental and clinical data, This information allows us to gain insi ghts into the three-dimensional structure of PS that will be helpful f or the design of new experiments and future clinical investigations, ( C) 1997 Wiley-Liss, Inc.