Vitamin K-Dependent Transmembrane Gla Proteins

维生素 K 依赖性跨膜 Gla 蛋白

• 批准号: 7163000
• 负责人: EARL W DAVIE
• 金额: $ 28.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2008-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163000
• 关键词: 1-Carboxyglutamic Acid; Adult; Biological; Blood coagulation; Bone Resorption; C2 Domain; Cell membrane; Chromosomes, Human, Pair 19; Endoplasmic Reticulum; Event; Fetus; Genes; Goals; Integral Membrane Protein; Investigation; Mammalian Cell; Physiological; Play; Post-Translational Protein Processing; Protein Binding; Protein Family; Proteins; Range; Reaction; Regulation; Role; Screening procedure; Specificity; Tissues; Translations; Ubiquitin; Ubiquitination; Vertebrates; Vitamin K; Warfarin; X Chromosome; Yeasts; gamma-glutamyl carboxylase; insight; member; mineralization; novel; size; ubiquitin-protein ligase; yeast two hybrid system

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 gamma- carboxyglutamic 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 Nedd4-1ike proteins, suggesting that they may play a role in the ubiquitin cycle. Nedd4-1ike 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.

维生素K依赖性蛋白质已被证明在脊椎动物的血液凝固和凝血中起主要作用。 其调节以及骨吸收和组织矿化。维生素K依赖蛋白 含有γ-羧基谷氨酸残基，其在翻译后事件中产生， 内质网腔。该反应由γ-谷氨酰羧化酶催化， 广泛分布于许多脊椎动物和非脊椎动物组织中。这次调查将集中在获得 深入了解四种新型维生素K依赖性蛋白的生物学作用， proteins.这些蛋白质的大小范围为17 kDa至25 kDa，并含有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。两个基因 在这些跨膜蛋白中，PRGP 1和TMG 3位于X染色体上，而PRGP 1和TMG 3的基因位于X染色体上。 PRGP 2和TMG 4分别位于染色体19和11上。转染哺乳动物的研究 细胞现在已经表明，它们需要维生素K进行翻译后修饰， 华法林抑制。四个跨膜蛋白的羧基区结合Nedd 4 - 1样蛋白， 这表明它们可能在泛素循环中起作用。Nedd 4 - 1样蛋白有一个C2结构域， WW结构域和在泛素循环中作为E3泛素连接酶起作用的HECT结构域。的 这些反应的机理和特异性将在这些研究中详细检查。