Vitamin K-Dependent Transmembrane Gla Proteins

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DESCRIPTION (provided by applicant): Vitamin K-dependent proteins have been shown to play a major role in vertebrates in blood coagulation and its regulation, as well as in bone resorption and tissue mineralization. The vitamin K-dependent proteins contain gamma carboxyglutamic acid residues that are generated in a post-translation event within the lumen of the endoplasmic reticulum. This reaction is catalyzed by a gamma glutamyl carboxylase that is widely distributed in numerous vertebrate and non-vertebrate tissues. This investigation will focus on gaining insight into the biological role of four novel vitamin K-dependent proteins that are single transmembrane proteins. These proteins range in size from 17 kDa to 25 kDa and contain from nine to thirteen gammacarboxyglutamic acid residues. They have been called PRGP1, PRGP2, TMG3, and TMG4. Genes for two of these transmembrane proteins, PRGP1 and TMG3 are located on the X chromosome, while genes for PRGP2 and TMG4 are found on chromosome 19 and 11, respectively. Studies with transfected mammalian cells have now shown that they require vitamin K for their post-translational modification in a reaction that is inhibited by warfarin. The carboxyl region of the four transmembrane proteins bind to Nedd4-like proteins, suggesting that they may play a role in the ubiquitin cycle. Nedd4-like proteins have a C2 domain, two to four WW domains, and a HECT domain that functions as an E3 ubiquitin ligase in the ubiquitin cycle. The mechanism and specificity of these reactions will be examined in detail in these investigations.