先進的な計算から原子解像度でシグナル伝達タンパク質の活性化機構
1Graduate program in Biophysics and Department of Chemistry and Theoretical Chemical Institute, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA.
Journal of the American Chemical Society
|July 28, 2007
まとめ
計算シミュレーションにより,化学作用タンパク質Yの活性化メカニズムが明らかになりました. Tyr106の回転は低バリアプロセスであり,Thr87の位移にのみ依存するものではなく,シグナル伝達タンパク質の機能に関する新しい洞察を提供します.
科学分野:
- バイオケミストリー バイオケミストリー
- コンピュータ生物学 コンピュータ生物学
- 構造生物学 構造生物学とは
背景:
- ケモタキシスタンパク質Yのようなシグナル伝達タンパク質は,細胞のコミュニケーションに不可欠です.
- 従来の"Y-T カップリング"モデルは,リン酸化による応答調節器の活性化を記述する.
- 正確なアクティベーションメカニズムを理解することは,細胞の信号伝達経路を解読する鍵です.
研究 の 目的:
- 化学作用タンパク質Yの活性化メカニズムを高解像度で解明する.
- タンパク質活性化におけるThr87の移位とTyr106の回転の役割を調査する.
- 応答調節器の活性化に関する既存のモデルに挑戦し,改良する.
主な方法:
- 移行経路サンプリングを含む高度な計算技術.
- エネルギーバリアを決定するための無料エネルギーの計算.
- 160以上の偏らない活性化軌道を分析した.
主要な成果:
- Tyr106の回転は低バリアプロセスであり,Thr87の位移に厳密に依存していない.
- Thr87-フォスファートの水素結合は,Tyr106の回転を安定させるが,それを可能にするだけではない.
- ベータ4-アルファ4ループの形状は,Tyr106の回転によって安定し,それによってゲートされない.
結論:
- この研究は,化学作用によるタンパク質Yの活性化に関する精巧なメカニズム的理解を提供します.
- 発見は従来の"Y-T カップリング"モデルに異議を唱え,Tyr106の固有の回転柔軟性を強調しています.
- 計算によるアプローチと洞察は,他のシグナル伝達タンパク質とアロステル系に適用できます.
関連する概念動画
01:30Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
01:16Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:24Intracellular Signaling Cascades
Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
01:26Signal Transduction: Overview
Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three...
Typically, signal transduction involves three...
01:48ATP Synthase: Mechanism
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP...