化调节的HIP-55动态相分离可以防止心力衰竭
Yunqi Jiang1,2,3, Jinge Gu4, Xiaodou Niu1,2,3
1Department of Cardiology and Institute of Vascular Medicine (Y.J., X.N., Y.Z., Y.T., Z.L.), Peking University Third Hospital, Beijing, China.
Circulation
|February 8, 2024
概括
化HIP-55 (血造基因酶1相互作用蛋白55kDa) 调节其液态相分离,防止心力衰竭. 这种机制对于预防心血管疾病的进展至关重要.
科学领域:
- 心血管生物学
- 疾病的分子机制
- 细胞生物物理学
背景情况:
- 心力衰竭是一种严重的心血管疾病,预后不佳,经济影响很大.
- 驱动HF病变的精确分子机制,特别是在压力下,仍然不完全理解.
- 研究新的分子途径为HF提供了潜在的治疗点.
研究的目的:
- 阐明HIP-55 (血造基因酶1相互作用蛋白55kDa) 在心力衰竭中的作用.
- 为了确定HIP-55的酸化调节液态相分离是否能提供对HF的保护.
- 在HF中探索HIP-55相分离和上腺体信号之间的分子相互作用.
主要方法:
- 在光漂白和差异干扰对比测试后利用光回收来评估HIP-55液态相分离.
- 在小鼠中使用基因操纵 (HIP-55删除和心脏过度表达) 来建模HF.
- 研究了在S269和T291位点的AKT介导化对HIP-55功能和HF进展的影响.
主要成果:
- 心脏特异性HIP-55的过度表达缓解了HF,而HIP-55的删除则加剧了它.
- HIP-55表现出强大的液相分离,通过AKT酸化在S269/T291进行动态调节.
- 在长期的交感过度活化下观察到失调的HIP-55阶段分离和聚合物形成,这有助于HF.
- HIP-55相分离抑制了β-上腺素受体介导的P38/MAPK信号通路.
结论:
- 化调节的HIP-55动态相分离是对交感/上腺系统中介心力衰竭的关键保护机制.
- 由于酸化受损导致异常HIP-55相分离导致HF.
- 针对HIP-55酸化和相分离可能为心力衰竭提供一种新的治疗策略.
相关概念视频
02:54Protein Kinases and Phosphatases
13.1K
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...
13.1K
01:02Phosphorylation
50.3K
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...
50.3K
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K
01:17Pathophysiology of Heart Failure
1.6K
Heart failure (HF) is a progressive syndrome involving ventricles that leads to inadequate cardiac output. It can be classified based on location and output or ejection fraction. Ejection fraction (EF) is an essential measurement in the diagnosis and surveillance of HF. Reduced EF corresponds to systolic heart failure (HFrEF). However, HF with preserved ejection fraction (HFpEF) is becoming increasingly prevalent. Also known as diastolic HF, this form of HF is related to aging. The...
1.6K
01:42Phosphoinositides and PIPs
8.5K
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
8.5K
01:22Amplifying Signals via Enzymatic Cascade
8.5K
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...
8.5K