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依赖性蛋白已显示在血液凝血中起主要作用 它的调节以及骨吸收和组织矿化。维生素K依赖性蛋白 包含在翻译后事件中产生的γ羧酸谷氨酸残基 内质网的腔。该反应是由γ谷氨酰基羧化酶催化的 广泛分布在众多脊椎动物和非脊椎动物组织中。这项调查将着重于获得 对四种新型维生素K依赖性蛋白的生物学作用的见解，这些蛋白是单跨膜 蛋白质。这些蛋白质的大小从17 kDa到25 kDa，含有从9到13个γ- 羧基谷氨酸残基。它们被称为PRGP1，PRGP2，TMG3和TMG4。两个基因 在这些跨膜蛋白中，PRGP1和TMG3位于X染色体上，而基因用于 PRGP2和TMG4分别在19和11染色体上发现。转染哺乳动物的研究 现在已经表明，它们需要维生素K进行翻译后修饰，这是 被华法林抑制。四种跨膜蛋白的羧基区域与NEDD4-1-kike蛋白结合， 表明它们可能在泛素周期中发挥作用。 NEDD4-1KIKE蛋白具有C2域，两到四个 WW域和在泛素周期中充当E3泛素连接酶的HECT域。这 这些反应的机制和特异性将在这些研究中进行详细研究。