基于能源格局的JAK1激活机制中研究多域运动的新方法
Shengjie Sun1,2, Georgialina Rodriguez3,4, Gaoshu Zhao5
1Department of Biomedical Informatic, School of Life Sciences, Central South University, Changsha 410083, China.
Briefings in bioinformatics
|March 6, 2024
概括
简氏激酶1 (JAK1) 的激活是热力学自发的. 抑制源于能量屏障,特别是氨酸激酶 (TK) 域从其腔中释放出来,揭示了JAK1激活机制.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 简氏激酶 (JAK) 家族通过JAK信号传感器和转录激活器 (STAT) 途径对细胞过程至关重要.
- 了解JAK激活,特别是从不活跃到活跃状态的过渡,是必不可少的,但仍然不完全理解.
研究的目的:
- 研究JAK1在激活过程中的静电特性和过渡状态.
- 阐明JAK1激活的机制和氨酸激酶 (TK) 域运动的作用.
主要方法:
- 抑制/激活的全长JAK1结构的建模.
- 在不同位置计算JAK1 Tyrosine Kinase (TK) 域能量.
- 应用Dijkstra的方法来确定最有利于激活的能量路径.
主要成果:
- 在热力学上,JAK1的激活是自发的.
- 抑制与最初激活步骤中的能量屏障有关,涉及TK域从FER (四点一,埃兹林,放射素,Moesin-PK) 域腔中释放.
- 对P733L和S703I突变的分析为JAK1调控提供了洞察力.
结论:
- 这项研究揭示了JAK1激活中TK域转位的潜在途径.
- 提供了对JAK1激活机制的洞察,强调了域释放和能量障碍的作用.
相关概念视频
The JAK-STAT Signaling Pathway
8.9K
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...
8.9K
Molecular Kinetic Energy
5.1K
The word "gas" comes from the Flemish word meaning "chaos," first used to describe vapors by the chemist J. B. van Helmont. Consider a container filled with gas, with a continuous and random motion of molecules. During collisions, the velocity component parallel to the wall is unchanged, and the component perpendicular to the wall reverses direction but does not change in magnitude. If the molecule’s velocity changes in the x-direction, then its momentum is changed.
5.1K
Protein Dynamics in Living Cells
2.1K
Different fluorescence-based techniques are used to study the protein dynamics in living cells. These techniques include FRAP, FRET, and PET.
Fluorescent recovery after photobleaching (FRAP) is a fluorescent-protein-based detection technique used to quantify protein movement rates within the cell. This method exposes a small portion of the cell to an intense laser beam. The laser beam causes permanent photobleaching of the fluorophore-tagged proteins in the exposed region. As the bleached...
Fluorescent recovery after photobleaching (FRAP) is a fluorescent-protein-based detection technique used to quantify protein movement rates within the cell. This method exposes a small portion of the cell to an intense laser beam. The laser beam causes permanent photobleaching of the fluorophore-tagged proteins in the exposed region. As the bleached...
2.1K
Protein-Drug Binding: Mechanism and Kinetics
470
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
470
Mechanisms of Membrane Domain Formation
3.0K
Different physical properties of lipids and proteins allow them to localize and form distinct islands or domains in the membrane. Some membrane domains are formed due to protein-protein interactions, whereas others are formed due to the presence of specific lipids such as sphingolipids and sterols—for example, large proteins, such as bacteriorhodopsin, aggregate and create distinct domains.
Another mechanism for membrane domain formation involves membrane proteins interacting with...
Another mechanism for membrane domain formation involves membrane proteins interacting with...
3.0K
cAMP-dependent Protein Kinase Pathways
6.3K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.3K


