GENE STRUCTURE OF VITAMIN K-DEPENDENT PROTEIN S; A REGION HOMOLOGOUS TO SEX HORMONE BINDING GLOBULIN (SHBG) REPLACES THE SERINE PROTEASE REGION OF FACTORS IX, X AND PROTEIN C

It has recently been shown that the similarity between coagulation factors IX, X and protein C in the protein sequence is also evident in the organization of their genes. To further elucidate the relation of protein S to the other vitamin K-dependent clotting factors, we are now characterizing the human protein S gene. The size of the gene was estimated to be more than 45 kb, by hybridization of a cDNA for human protein S with chromosomal DNA in a Southern blot.We have isolated three overlapping clones from a human genomic DNA library in bacteriophage λ Charon 4A, which cover approximately 40 kb of the gene. The clones have been mapped by single- and double restriction enzyme digestion. Genomic subclones in pUC 18 which hybridize with cDNA probes for protein S have been isolated and sequenced to establish the intron/exon structure of the gene. The 5’- part of the human protein S gene closely resembles the corresponding part of the genes for factors IX, X and protein C. However, the thrombin sensitive region (amino acids 46-75), which is unique for protein S among the vitamin K-dependent clotting factors, is coded for by a separate exon. The 3'- end of the protein S gene, coding for amino acids 247-635, is not homologous to the catalytic region of the vitamin K-dependent serine proteases but shows a significant homology to human sex hormone binding globulin (SHBG).