Vitamin K-Dependent Transmembrane Gla Proteins

描述（由申请人提供）：维生素K依赖性蛋白已被证明在脊椎动物的血液凝固及其调节以及骨吸收和组织矿化中发挥重要作用。维生素K依赖性蛋白含有γ羧基谷氨酸残基，其在内质网腔内的翻译后事件中产生。该反应由广泛分布于许多脊椎动物和非脊椎动物组织中的γ-谷氨酰羧化酶催化。这项研究将集中在深入了解四种新的维生素K依赖性蛋白的生物学作用，这些蛋白是单跨膜蛋白。这些蛋白质的大小范围为17 kDa至25 kDa，含有9至13个γ-羧基谷氨酸残基。它们被称为PRGP 1、PRGP 2、TMG 3和TMG 4。这些跨膜蛋白中的两种，PRGP 1和TMG 3的基因位于X染色体上，而PRGP 2和TMG 4的基因分别位于染色体19和11上。对转染的哺乳动物细胞的研究表明，它们需要维生素K进行翻译后修饰，而这种修饰反应可被华法林抑制。四个跨膜蛋白的羧基区域结合Nedd 4样蛋白，表明它们可能在泛素循环中发挥作用。Nedd 4样蛋白具有C2结构域、2至4个WW结构域和HECT结构域，其在泛素循环中作为E3泛素连接酶起作用。这些反应的机制和特异性将在这些调查中详细检查。

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.