通过与cGMP依赖的蛋白激酶Ialpha的特定相互作用来调节肌酸酸酶
H K Surks1, N Mochizuki, Y Kasai
1Molecular Cardiology Research Institute and Cardiology Division, Department of Medicine, Tufts University School of Medicine and New England Medical Center, Boston, MA 02111, USA.
概括
循环氨酸单酸依赖蛋白激酶Ialpha (cGKIalpha) 通过肌结合子单元 (MBS) 相互作用准平滑肌肉收缩器官. 这种相互作用对于通过控制肌素轻链脱酸化来调节血管光滑肌肉度至关重要.
科学领域:
- 分子生物学分子生物学
- 细胞生理学 细胞生理学
- 生物化学 生物化学
背景情况:
- 滑动肌肉的收缩/放松是由肌轻链激酶和酸酶控制的.
- 循环氨酸单酸盐 (cGMP) 依赖蛋白激酶Ialpha (cGKIalpha) 是血管平滑肌肉放松的关键.
- 氧化 (NO) 和cGMP通路调节血管度.
研究的目的:
- 阐明cGKIalpha调节血管光滑肌肉度的机制.
- 为了确定调解cGKIalpha在收缩器官中的功能的特定相互作用.
- 为了证明这种相互作用对于生理平滑肌肉放松的必要性.
主要方法:
- 研究了cGKIalpha和肌酸酸酶子单元之间的相互作用.
- 使用生物化学分析来确认氨酸的拉链介导结合.
- 研究了干扰cGKIalpha-MBS相互作用对髓轻链酸化的功能后果.
主要成果:
- cGKIalpha通过一个氨酸拉链图案直接与氨酸酸酶的髓结合子单元 (MBS) 结合.
- 这种相互作用成功地将cGKIalpha向平滑肌肉收缩装置.
- 干扰cGKIalpha-MBS相互作用取消了cGMP依赖的肌素光链的脱化.
结论:
- cGKIalpha和MBS之间的相互作用对于将激酶向其作用部位至关重要.
- 这种特定的相互作用对于血管光滑肌肉度的生理调节至关重要.
- 了解这种机制可以了解光滑肌肉中NO/cGMP信号传递的情况.
相关概念视频
GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
G-Protein Gated Ion Channels
GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory organs,...
Sensory organs,...
GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
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,...


