Vitamin K-Dependent Transmembrane Gla Proteins

维生素 K 依赖性跨膜 Gla 蛋白

• 批准号: 6556832
• 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/6556832
• 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

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.

描述（由申请人提供）：已证明维生素K依赖性蛋白在血液凝结及其调节以及骨吸收和组织矿化中起着主要作用。维生素K依赖性蛋白含有γ羧酸谷氨酸残基，这些残基是在内质网的腔内在翻译后事件中产生的。该反应是由广泛分布在众多脊椎动物和非脊椎动物组织中的γ谷氨酰基羧化酶催化的。这项研究将着重于洞悉单个跨膜蛋白的四种新型维生素K依赖性蛋白的生物学作用。这些蛋白质的大小从17 kDa到25 kDa，含有从9至13个γ羧酸谷氨酸残基。它们被称为PRGP1，PRGP2，TMG3和TMG4。这些跨膜蛋白中的两个基因PRGP1和TMG3位于X染色体上，而PRGP2和TMG4的基因分别在19和11染色体上发现。对转染的哺乳动物细胞的研究现已表明，在华法林抑制的反应中，它们需要维生素K进行翻译后修饰。四种跨膜蛋白的羧基区域与NEDD4样蛋白结合，表明它们可能在泛素周期中起作用。 NEDD4样蛋白具有C2结构域，2至4个WW结构域，并且在泛素周期中充当E3泛素连接酶的HECT域。这些反应的机制和特异性将在这些研究中进行详细研究。