Structural and functional implications of the intron exon organization of the human endothelial cell protein C activated protein C receptor (EPCR) gene: Comparison with the structure of CD1/major histocompatibility complex alpha 1 and alpha 2 domains

The endothelial cell protein C/activated protein C receptor (EPCR) is locat ed primarily on the surface of the large vessels of the vasculature. In vit ro studies suggest that it is involved in the protein C anticoagulant pathw ay. We report the organization and nucleotide sequence of the human EPCR ge ne. It spans approximately 6 kbp of genomic DNA, with a transcription initi ation point 79 bp upstream of the translation initiation (Met) codon in clo se proximity to a TATA box and other promoter element consensus sequences. The human EPCR gene has been localized to 20q11.2 and consists of four exon s interrupted by three introns, all of which obey the GT-AG rule. Exon I en codes the 5' untranslated region and the signal peptide, and exon IV encode s the transmembrane domain, the cytoplasmic tail, and the 3' untranslated r egion. Exons II and III encode most of the extracellular region of the EPCR . These exons have been found to correspond to those encoding the alpha 1 a nd alpha 2 domains of the CD1/major histocompatibility complex (MHC) class I superfamily. Flanking and intervening introns are of the same phase (phas e I) and the position of the intervening intron is identically located. Sec ondary structure prediction for the amino acid sequence of exons II and III corresponds well with the actual secondary structure elements determined f or the oil and alpha 2 domains of HLA-A2 and murine CD1.1 from crystal stru ctures. These findings suggest that the EPCR folds with a P-sheet platform supporting two a-helical regions collectively forming a potential binding p ocket for protein C/activated protein C. (C) 1999 by The American Society o f Hematology.