Vitamin K-Dependent Transmembrane Gla Proteins

维生素 K 依赖性跨膜 Gla 蛋白

• 批准号: 6827864
• 负责人: EARL W DAVIE
• 金额: $ 30.32万
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827864
• 关键词: blood coagulation; calcium binding protein; gene targeting; genetically modified animals; laboratory mouse; membrane proteins; molecular genetics; posttranslational modifications; protein structure function; ubiquitin; vitamin K; yeast two hybrid system

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。维生素 K 依赖性蛋白已被证明在脊椎动物的凝血及其调节以及骨吸收和组织矿化中发挥着重要作用。维生素 K 依赖性蛋白含有 γ 羧基谷氨酸残基，在内质网腔内的翻译后事件中产生。该反应由广泛分布于众多脊椎动物和非脊椎动物组织中的γ谷氨酰羧化酶催化。这项研究将重点深入了解四种新型维生素 K 依赖性蛋白质（单跨膜蛋白质）的生物学作用。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 PRGP1、PRGP2、TMG3 和 TMG4。其中两种跨膜蛋白 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 号和 11 号染色体上。对转染哺乳动物细胞的研究现已表明，它们需要维生素 K 来进行翻译后修饰，而华法林会抑制该反应。四种跨膜蛋白的羧基区域与 Nedd4-1ike 蛋白结合，表明它们可能在泛素循环中发挥作用。 Nedd4-1ike 蛋白具有一个 C2 结构域、两到四个 WW 结构域和一个在泛素循环中充当 E3 泛素连接酶的 HECT 结构域。这些反应的机制和特异性将在这些研究中进行详细检查。表演网站==========================================章节结束===============================================