Rasアクティベーターの自己抑制の構造分析 Son of sevenlesslessの息子
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
まとめ
セブンレス (SOS) タンパク質の息子
科学分野:
- 分子生物学は分子生物学である.
- 細胞シグナル伝達 細胞信号伝達
- タンパク質の構造と機能
背景:
- クラシックモデルでは,膜の採用とRasのエンゲージメントによる7less (SOS) の活性化について説明しています.
- 最近の発見は,Ras*GTPがアロステリック活性化剤であることを明らかにし,より複雑なSOS調節を示す.
- SOS規制を理解することは,Ras媒介のシグナル伝達経路の解読に不可欠です.
研究 の 目的:
- SOS調節におけるDblホモロジー-プレックストリンホモロジー (DH-PH) ドメインの構造的および機能的役割を明らかにする.
- Ras結合に反応して,DH-PHユニットがSOS活動をどのように調節するかを調査する.
- ヌクレオチド交換中のRasとSOSの相互相互作用を明確にするために.
主な方法:
- 鍵となるSOS構造物の結晶学分析.
- SOS活動とRas結合を評価するための生化学的測定法.
- SOSのDH-PHと触媒領域に焦点を当てた構造研究.
主要な成果:
- SOSのDH-PHユニットは,アロステリックRas結合部位を物理的にブロックすることが判明しました.
- DH-PHユニットによるこの阻害は,SOSの基礎活性を抑制する.
- SOSの活動はRas結合によって調節され,Ras*GDPは低活性化,Ras*GTPは最大活性化を行う.
結論:
- DH-PHドメインは自己抑制要素として作用し,SOSの活性化を調節する.
- アロステリック部位へのRas結合は,SOS活性度の低い状態と高い状態の両方に不可欠です.
- DH-PHユニットは,RasがSOS媒介のヌクレオチド交換を促進する相互活性化メカニズムをゲートします.
関連する概念動画
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...