ATPに競合する薬剤でキナーゼ活性をバイパスする
Feroz R Papa1, Chao Zhang, Kevan Shokat
1Department of Medicine, University of California, San Francisco, CA 94143-2200, USA. frpapa@medicine.ucsf.edu
Science (New York, N.Y.)
|October 18, 2003
まとめ
展開タンパク質応答 (UPR) は,エンドプラズマ網膜のストレスによって誘発されます. Ire1キナーゼドメインの活性化には,驚くべきことに,UPRを誘発するには,リン酸化ではなく,リガンドコファクターが必要です.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- バイオケミストリー バイオケミストリー
背景:
- エンドプラズマ網膜 (ER) の未折れたタンパク質は,トランスメブランキナーゼ Ire1.1.を活性化させます.
- Ire1の活性化は,エンドロビヌクレアースの活性化とHAC1mRNAの非従来のスプライシングにつながります.
- このプロセスは,展開タンパク質応答 (UPR) を開始します.
研究 の 目的:
- UPR活性化におけるIre1のキナーゼドメインの役割を調査する.
- 化学阻害剤を用いたIre1活性化のメカニズムを探求する.
主な方法:
- 1NM-PP1.1へのIre1キナーゼドメインの感受性を高めるためのサイト指向型変異.
- Ire1活性化のためのコファクターとしてATP競争性阻害剤1NM-PP1を使用する.
- 薬剤に敏感なIRE1変異体におけるUPR誘導の評価.
主要な成果:
- 1NM-PP1に敏感な変異種Ire1は,逆説的に,抑制ではなく活性化のために薬を必要とした.
- 1NM-PP1はコファクターとして作用し,キナーゼ変異の不活性化でもIre1の活性化を可能にしました.
- アクティベーションされたIre1は完全なUPRを誘導し,キナーゼ活性への必要性を回避した.
結論:
- Ire1の活性化は,リガンド結合時にキナーゼ領域の構造変化によって引き起こされます.
- リン酸化ではなく,活性部位のリガンド占有が,Ire1の下流機能を活性化するための鍵です.
- この発見は,IRE1シグナリングによるUPR開始のメカニズムを再定義します.
関連する概念動画
01:08Hydrolysis of ATP
The bonds of adenosine triphosphate (ATP) can be broken through the addition of water, releasing one or two phosphate groups in an exergonic process called hydrolysis. This reaction liberates the energy in the bonds for use in the cell—for instance, to synthesize proteins from amino acids.
If one phosphate group is removed, a molecule of ADP—adenosine diphosphate—remains, along with inorganic phosphate. ADP can be further hydrolyzed to AMP—adenosine monophosphate—by the removal of a second...
If one phosphate group is removed, a molecule of ADP—adenosine diphosphate—remains, along with inorganic phosphate. ADP can be further hydrolyzed to AMP—adenosine monophosphate—by the removal of a second...
01:08Hydrolysis of ATP
The bonds of adenosine triphosphate (ATP) can be broken through the addition of water, releasing one or two phosphate groups in an exergonic process called hydrolysis. This reaction liberates the energy in the bonds for use in the cell—for instance, to synthesize proteins from amino acids.
If one phosphate group is removed, a molecule of ADP—adenosine diphosphate—remains, along with inorganic phosphate. ADP can be further hydrolyzed to AMP—adenosine monophosphate—by the removal of a second...
If one phosphate group is removed, a molecule of ADP—adenosine diphosphate—remains, along with inorganic phosphate. ADP can be further hydrolyzed to AMP—adenosine monophosphate—by the removal of a second...
01:27ATP Driven Pumps I: An Overview
ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
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...
01:18ATP Synthase: Structure
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
01:14Active Transport
Active transport is a critical biological process that allows cells to move solutes against an electrochemical gradient. This process requires direct energy input and is characterized by its selectivity, saturability, and susceptibility to competitive inhibition.
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...