马科维亚状态模型揭示了控制昼夜周期的素激酶1动态
Clarisse Gravina Ricci1,2, Jonathan M Philpott3, Megan R Torgrimson3
1Department of Chemistry and Biochemistry, University of California San Diego, San Diego, California, United States.
bioRxiv : the preprint server for biology
|February 3, 2025
概括
素激酶1 (CK1) 通过酸化周期 (PER) 蛋白调节昼夜节律. 突变改变了CK1的情况.
科学领域:
- 生物化学 生物化学
- 时间生物学 时间生物学
- 分子生物学分子生物学
背景情况:
- 在哺乳动物中,循环节律是通过周期蛋白酸化 (PER) 通过素激酶1 (CK1) 控制的.
- CK1在不同的区域化PER蛋白,影响PER降解 (降解) 或稳定 (家族高级睡眠阶段 - FASP区域).
- 了解CK1的基质选择性机制对于破译昼夜节律调节至关重要.
研究的目的:
- 调查CK1的结构动力学如何决定其基质选择性.
- 为了建模野生型和突变性CK1 (tau R178C) 的构造景观.
- 阐明突变影响CK1活性和PER蛋白相互作用的机制.
主要方法:
- 广泛的分子动力学 (MD) 模拟野生型和tau突变CK1.1.
- 构建马科维国家模型 (MSM) 来分析模拟数据.
- 斯加速分子动力学 (GaMD) 用于建模CK1-FASP相互作用.
主要成果:
- 陶突变改变了CK1的激活环形状,加速了它的动态.
- 这种形状变化损害了FASP动机结合,导致PER不稳定.
- 鉴定出一种可以调节CK1活动的全囊囊.
结论:
- CK1的激活循环充当控制基质选择性的分子开关.
- 突变通过改变CK1的结构动态和基质结合来破坏昼夜时间.
- 针对已识别的全囊口袋,为昼夜节律障碍提供了潜在的治疗策略.
相关概念视频
Circadian Rhythms and Gene Regulation
4.0K
The biological clock is involved in many aspects of regulating complex physiology in all animals. It was in 1935 when German zoologists, Hans Kalmus and Erwin Bünning, discovered the existence of circadian rhythm in Drosophila melanogaster. However, the internal molecular mechanisms behind the circadian clock remained a mystery until 1984, when Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered the expression of the Per gene oscillating over a 24-hour cycle. In subsequent...
4.0K
Calmodulin-dependent Signaling
5.1K
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,...
5.1K
MAPK Signaling Cascades
5.1K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.1K
Positive Regulator Molecules
5.3K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.3K
M-Cdk Drives Transition Into Mitosis
5.5K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.5K


