突变扫描精确指出了ATGL关键调节器在脂解中的独特结合点
Johanna M Kohlmayr1, Gernot F Grabner2,3, Anna Nusser1
1Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Graz, Austria.
Nature communications
|March 22, 2024
概括
这项研究绘制了脂肪三糖 lipase (ATGL) 中单氨基酸的变化如何影响其与调节蛋白的相互作用,揭示了特定的"开关"突变,这些突变精确地改变了脂解控制. 这些发现提供了对代谢和心血管疾病机制的见解.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 脂肪三甘油脂酶 (ATGL) 是细胞内脂解的核心,该过程对能量稳态至关重要,并与代谢和心血管疾病有关.
- 通过与调节蛋白的相互作用,ATGL的活性被精确控制,包括CGI-58,G0S2,PLIN1,PLIN5和CIDEC.
研究的目的:
- 综合地绘制单氨基酸变体对ATGL与其关键监管合作伙伴的相互作用的影响.
- 识别和描述高度选择性的ATGL突变,这些突变特别扰乱了与个体合作伙伴的相互作用.
主要方法:
- 使用深度突变蛋白相互作用扰动扫描来生成变异形状.
- 哺乳动物细胞的共同免疫沉实验验验证了相互作用的变化.
- 在体外甘油三酶活性测定和细胞脂解测量评估了功能后果.
主要成果:
- 23种ATGL变种显示出与监管合作伙伴的特定相互作用扰动模式.
- 确定了11种高度选择性的ATGL"开关"突变,影响单个伴侣相互作用而不影响其他伴侣.
- ATGL开关变体的功能活性与它们的蛋白质相互作用概况直接相关.
结论:
- 特定的氨基酸残留物作为ATGL与其调节蛋白的相互作用的独特决定因素.
- 这些开关突变提供了对脂解调节的高分辨率理解.
- 这些发现揭示了ATGL突变对人类代谢和心血管疾病的影响.
相关概念视频
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
01:19Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K