Function and regulation of the novel Ras-subfamily guanine nucleotide-releasing factor very-KIND

Ras GTP酶被鸟嘌呤核苷酸交换因子（GEFs）激活，该因子催化蛋白质转移到活性GTP结合形式。我们最近发现了新的RasGEF very-KIND，它在n端编码两个激酶非催化C-lobe结构域（KIND），在c端编码RasGEFN和RasGEF结构域。KIND结构域与c端蛋白激酶折叠结构相似。它可能从催化蛋白激酶结构域进化为蛋白质相互作用结构域。小鼠very-KIND基因仅在发育和成年神经系统中表达。它在脊椎动物中的有限表达表明，该基因在高等生物复杂的神经系统中具有非常特殊的功能。本文拟通过实验分析RasGEF very-KIND的功能和调控。我们计划确定哪些Ras GTPases被very- KIND和调节交换因子活性的信号激活。我们对KIND基序的功能特别感兴趣，它可能通过信号蛋白的吸引来调节交换因子的活性。产生非常kind缺陷的小鼠应该有助于了解该基因在小鼠神经系统中的作用，也将对了解该蛋白的细胞生物学功能至关重要。

Ras GTPases are activated by guanine nucleotide exchange factors (GEFs), which catalyze the transfer of the proteins into the active GTP bound form. We recently have discovered the novel RasGEF very-KIND, which encodes two kinase non-catalytical C-lobe domains (KIND) in its N-terminal part and RasGEFN and RasGEF domains in the C-terminal part. The KIND domain has structural similarities to the C-terminal protein kinase fold. It potentially evolved from the catalytic protein kinase domain into a protein interaction domain. The mouse very-KIND gene is exclusively expressed in the developing and adult nervous system. Its limited expression in vertebrates points towards a very specified function of the gene in the sophisticated nervous systems of higher organisms. Here we propose experiments to analyse the function and regulation of the RasGEF very-KIND. We plan to determine, which Ras GTPases are activated by very- KIND and the signals regulating the activity of the exchange factor. We are specifically interested in the function of the KIND motifs, which might regulate the activity of the exchange factor by the attraction of signalling proteins. The generation of very-KIND deficient mice should help to understand role of the gene in the mouse nervous system and will also be essential for the understanding of the cell biological function of the protein.