Rac特異のGAP,β2-キマエリンの脂質活性化のための構造的メカニズム
Bertram Canagarajah1, Federico Coluccio Leskow, Jonathan Yew Seng Ho
1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA.
Cell
|October 28, 2004
まとめ
ディアシルグリセロール結合は,抑制相互作用を妨害することによってβ2-キメアリンを活性化します. この構造的研究は,フォスフォリピド結合がRac GTPase活性化タンパク質のロックを解除し,Rac結合と酵素活性化を可能にする方法を示しています.
科学分野:
- バイオケミストリー バイオケミストリー
- 構造生物学 構造生物学とは
- 細胞シグナル伝達 細胞信号伝達
背景:
- ディアシルグリセロール (DAG) は脂質第2メッセンジャーです.
- DAGは標的タンパク質のC1ドメインと結合し,細胞膜への転位およびアロステル活性化を誘導する.
- ベータ2キマエリンは,小さなGTPase Rac.のGTPase活性化タンパク質 (GAP) である.
研究 の 目的:
- ベータ2キマエリンの不活性構成の結晶構造を決定する.
- ダイアシルグリセロールとフォスフォリピドによるβ2-キメラリン調節の基礎となる分子機構を解明する.
主な方法:
- 3.2 Åの解像度のX線結晶学.
- タンパク質とタンパク質,およびタンパク質と脂質の相互作用の構造分析.
主要な成果:
- 非活性β2-キメアリン構造は,RacGAP活性部位をブロックするN端を明らかにします.
- C1ドメインの脂質結合部位は,複数のタンパク質領域との相互作用によって遮られる.
- フォスフォリピドがC1ドメインに結合すると,これらの抑制相互作用が解離する.
結論:
- C1ドメインへのフォスフォリピド結合は,β2-キメラリン活性化を開始する重要なイベントです.
- 抑制要素の解離により,N端が活性部位のブロックを解除し,RacGAPの活性が活性化されます.
- この研究は,C1ドメインを含むタンパク質のアロステル活性化メカニズムに関する構造的な洞察を提供します.
関連する概念動画
Rab Proteins
Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab Cascades
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
Small 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:
TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...


