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 alpha1 and alpha2 domains.
The endothelial cell protein C/activated protein C receptor (EPCR) is located primarily on the surface of the large vessels of the vasculature. In vitro studies suggest that it is involved in the protein C anticoagulant pathway. We report the organization and nucleotide sequence of the human EPCR gene. It spans approximately 6 kbp of genomic DNA, with a transcription initiation point 79 bp upstream of the translation initiation (Met) codon in close 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 exons interrupted by three introns, all of which obey the GT-AG rule. Exon I encodes the 5' untranslated region and the signal peptide, and exon IV encodes the transmembrane domain, the cytoplasmic tail, and the 3' untranslated region. Exons II and III encode most of the extracellular region of the EPCR. These exons have been found to correspond to those encoding the alpha1 and alpha2 domains of the CD1/major histocompatibility complex (MHC) class I superfamily. Flanking and intervening introns are of the same phase (phase I) and the position of the intervening intron is identically located. Secondary structure prediction for the amino acid sequence of exons II and III corresponds well with the actual secondary structure elements determined for the alpha1 and alpha2 domains of HLA-A2 and murine CD1.1 from crystal structures. These findings suggest that the EPCR folds with a beta-sheet platform supporting two alpha-helical regions collectively forming a potential binding pocket for protein C/activated protein C.
Simmonds
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Department of Haematology, Imperial College School of Medicine, London, UK. r.simmonds@ic.ac.uk
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D000595:Amino Acid Sequence; D018949:Antigens, CD1 / Q000235:genetics*; D001483:Base Sequence; D001779:Blood Coagulation Factors; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005796:Genes; D005805:Genes, MHC Class I; D015789:HLA-A2 Antigen / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D017385:Sequence Homology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D018949:Antigens, CD1; D001779:Blood Coagulation Factors; D003062:Codon; D018076:DNA, Complementary; D015789:HLA-A2 Antigen; D011956:Receptors, Cell Surface; C091963:activated protein C receptor