Vitamin K-Dependent Transmembrane Gla Proteins

描述(申请人提供)：维生素K依赖的蛋白质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主要作用。依赖维生素K的蛋白质含有伽马羧基谷氨酸残基，这些残基是在内质网腔内的翻译后事件中产生的。这一反应是由一种广泛分布于许多脊椎动物和非脊椎动物组织中的伽马谷氨酰羧基酶催化的。这项研究将集中于深入了解四种新的维生素K依赖蛋白的生物学作用，这些蛋白是单一的跨膜蛋白。这些蛋白质的大小从17 kDa到25 kDa不等，含有9到13个伽马羧基谷氨酸残基。它们被称为PRGP1、PRGP2、TMG3和tMG4。其中两个跨膜蛋白PRGP1和TMG3的基因位于X染色体上，而PRGP2和tmG4的基因分别位于19和11号染色体上。对转基因哺乳动物细胞的研究现在表明，它们需要维生素K来进行翻译后修饰，而华法林可以抑制这种反应。这四种跨膜蛋白的羧基区域与Nedd4样蛋白结合，提示它们可能在泛素循环中发挥作用。类Nedd4蛋白有一个C2结构域、两到四个WW结构域和一个Hect结构域，在泛素循环中作为E3泛素连接酶发挥作用。在这些调查中，将详细研究这些反应的机理和特异性。

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.