通过酸化和Ca2调节人类酸化酶激酶的分子基础
Ruifang Ma1, Bowen Du1, Chen Shi2,3
1Shenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
Nature communications
|March 28, 2025
概括
酸酶激酶 (PhK) 结构在使用冷电子显微镜的无活性和活性状态中得到解决. 这揭示了酸化和Ca2+如何激活PhK,提供了对Glycogen Storage Disease type IX和癌症的见解.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子医学是分子医学.
背景情况:
- 酶激酶 (PhK) 对于糖原分解至关重要,调节能量供应.
- PhK功能障碍与糖原储存疾病第九型 (GSD IX) 和瘤发生有关.
研究的目的:
- 阐明PhK在非活性和活性状态中的近原子结构.
- 了解PhK激活和基质结合的分子机制.
主要方法:
- 电子显微镜 (cryo-EM) 用于结构的确定.
- 交联质谱法 (XL-MS) 用于分析PhK-基质相互作用.
主要成果:
- 解决了非活性和活性PhK复合物的近原子结构,详细说明了子单元相互作用 (αβγδ).
- α和β子单元的酸化压缩了PhK,而Ca2+诱导了δ子单元的滑动,协同激活了γ子单元.
- 在不同状态下,在PhK和糖原酸化酶 (GP) 之间确定了不同的结合模式.
结论:
- 对PhK激活机制的结构洞察力为理解GSD IX提供了基础.
- 了解PhK调节为癌症研究和治疗策略提供了潜在的途径.
相关概念视频
Phosphorylation
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
Phosphorylation
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
cAMP-dependent Protein Kinase Pathways
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,...
Calmodulin-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,...


