在Ras激活器中自抑制的结构分析Sevenlessless的儿子
Holger Sondermann1, Stephen M Soisson, Sean Boykevisch
1Howard Hughes Medical Institute, Department of Molecular and Cell Biology and Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Cell
|October 28, 2004
概括
七无 (SOS) 蛋白质的儿子
科学领域:
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
- 蛋白质结构和功能 蛋白质结构和功能
背景情况:
- 经典模型描述了通过膜招募和Ras参与的无七子 (SOS) 激活.
- 最近的发现揭示了Ras*GTP作为质激活剂,表明更复杂的SOS调节.
- 了解SOS调节对于破译Ras介导的信号通路至关重要.
研究的目的:
- 阐明在SOS调节中的Dbl同质 - 链同质 (DH-PH) 域的结构和功能作用.
- 调查DH-PH单元如何调节SOS活动以响应Ras结合.
- 为了澄清核酸交换期间Ras和SOS之间的相互相互作用.
主要方法:
- 一个关键的SOS结构的晶体分析.
- 生物化学测定以评估SOS活性和Ras结合.
- 结构研究侧重于SOS的DH-PH和催化领域.
主要成果:
- 发现SOS的DH-PH单元在物理上阻断了全性Ras结合部位.
- 这种DH-PH单元的阻塞抑制了SOS的基础活性.
- 通过Ras结合来调节SOS活动,Ras*GDP使活动较低,Ras*GTP使活动最大.
结论:
- DH-PH 域作为一种自我抑制的元素,调节SOS激活.
- 在低和高SOS活性状态下,Ras与全位的结合是必不可少的.
- DH-PH单元关闭一个互惠激活机制,Ras促进SOS介导的核酸交换.
相关概念视频
00:46Feedback Inhibition
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
02:36RNA Polymerase II Accessory Proteins
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...