通过与ATP竞争的药物绕过激酶活性
Feroz R Papa1, Chao Zhang, Kevan Shokat
1Department of Medicine, University of California, San Francisco, CA 94143-2200, USA. frpapa@medicine.ucsf.edu
概括
展开的蛋白质反应 (UPR) 是由内质网膜压力触发的. 令人惊的是,Ire1激酶域激活需要一个联体辅因子,而不是酸化,以诱导UPR.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 细胞内膜网膜 (ER) 中未折叠的蛋白质激活了跨膜激酶Ire1.1.
- Ire1的激活导致内啡核糖酶的活性和HAC1mRNA的非传统拼接.
- 这个过程启动了未折叠蛋白质反应 (UPR).
研究的目的:
- 研究Ire1的激酶域在UPR激活中的作用.
- 使用化学抑制剂探索Ire1激活的机制.
主要方法:
- 位点定向的突变发生使Ire1激酶域对1NM-PP1.1产生敏感.
- 使用ATP竞争性抑制剂1NM-PP1作为Ire1激活的辅因子.
- 评估药物敏感的Ire1突变体中的UPR诱导.
主要成果:
- 突变Ire1,对1NM-PP1敏感,矛盾的是,需要药物来激活,而不是抑制.
- 1NM-PP1充当了辅助因子,使Ire1的激活成为可能,即使在非激活酶突变的情况下也是如此.
- 激活的Ire1诱导了完整的UPR,绕过了对激酶活性的需求.
结论:
- Ire1的激活是由酶域在连接物结合时的形态变化引发的.
- 活跃部位的联体占用,而不是酸化,是激活Ire1下游功能的关键.
- 这一发现重新定义了通过Ire1信号发送启动UPR的机制.
相关概念视频
Hydrolysis 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...
Hydrolysis 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...
ATP 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...
ATP 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...
ATP 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...
Active 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...


