通过cAMP/PKA和cGMP/PKGG促进蛋白质稳定
Md Salim Ahammed1, Xuejun Wang1
1Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD 57069, USA.
Trends in molecular medicine
|October 30, 2024
概括
蛋白质酶功能不充分导致神经退行和心力衰竭. 激活蛋白激酶A (PKA) 和PKG可以通过增强无素-蛋白酶系统 (UPS) 和清除错误折叠的蛋白质来打破这个循环.
科学领域:
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
- 心脏病学 心脏病学
背景情况:
- 蛋白质体功能不充分 (PFI) 与神经退行性疾病和心力衰竭有关.
- 异常的蛋白质聚合损害了泛素蛋白酶体系统 (UPS),增加了蛋白质毒性压力 (IPTS).
- 这就形成了一个有害的循环,加剧了疾病的进展.
研究的目的:
- 审查蛋白质激酶A (PKA) 和蛋白质激酶G (PKG) 在通过UPS调节蛋白质稳定中的作用.
- 探索治疗与增加蛋白质毒性压力 (IPTS) 相关的疾病的策略.
- 讨论针对性PKA和PKG激活对治疗益处的潜力.
主要方法:
- 对PKA,PKG,UPS和蛋白质稳定性研究的文献综述.
- 分析PKA和PKG影响蛋白酶体活性的机制.
- 对涉及PFI和IPTS的疾病的治疗影响的讨论.
主要成果:
- 通过酸化RPN6/PSMD11.11,PKA激活了蛋白酶体.
- 已知PKG会激活蛋白酶体,但其精确的机制仍需要阐明.
- 增强cAMP/PKA和cGMP/PKG信号通路显示出治疗IPTS相关疾病的前景.
结论:
- 在蛋白质酶纳米域中向激活PKA和PKG可以提供治疗策略.
- 这种方法可以最大限度地减少非目标效应,同时增强蛋白质酶的功能.
- 调节PKA和PKG为打破PFI相关疾病恶性循环提供了一个潜在的途径.
相关概念视频
cAMP-dependent Protein Kinase Pathways
6.1K
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,...
6.1K
PI3K/mTOR/AKT Signaling Pathway
3.4K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.4K
Amplifying Signals via Enzymatic Cascade
8.3K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.3K
GPCRs Regulate Adenylyl Cylase Activity
5.3K
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...
5.3K
Global Regulatory Systems
2
Global regulatory systems in bacteria enable rapid and coordinated responses to environmental changes by integrating sensory inputs with gene expression, ensuring efficient adaptation to fluctuating conditions. Key global regulatory mechanisms include regulons, two-component systems, sigma factors, and secondary messengers.Regulons and Global RegulatorsA regulon is a collection of genes and operons controlled by a common global regulator. These regulators enable bacteria to prioritize resource...
2
mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K


