500個のヒトタンパク質ドメインのサイト飽和変異
Antoni Beltran1, Xiang'er Jiang2,3,4, Yue Shen2,3,4
1Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Nature
|January 8, 2025
まとめ
この研究では50万種以上のヒトミセンスの変異を定量化し,病原性の変異の60%がタンパク質の安定性を低下させることを発見しました. この大規模なデータセットは,臨床的変異の解釈と計算方法の開発を助けます.
科学分野:
- 遺伝学
- 分子生物学
- 生物化学
背景:
- タンパク質のアミノ酸配列を 変えてしまうミッセンスの変種は 人間の遺伝疾患の3分の"を 引き起こします
- 現存する数百万のミッセンスの変異の機能的な影響は ほとんど不明のままである.
- 遺伝子変異の影響を理解することは 遺伝的疾患の診断と治療に不可欠です
研究 の 目的:
- 実験的に多数の人間のミセンス変異の機能的効果を定量化する.
- 変数解釈と計算ツール開発のための包括的なデータセットを確立する.
- ミッセンスの多様性の病原性におけるタンパク質の安定性の役割を調査する.
主な方法:
- 大規模なDNA合成と細胞選択実験が実施された.
- ヒトの500種類以上のタンパク質ドメインの多さに50万種類以上の影響が定量化されました.
- タンパク質の安定性測定は,タンパク質言語モデルとエネルギーモデルと統合された.
主要な成果:
- 60%の病原性ミッセンスの変種はタンパク質の安定性を低下させることが判明した.
- タンパク質の適性に対する安定性の貢献は,タンパク質と疾患によって,特に後退性疾患では異なる.
- 安定性に対する変異効果は同類ドメインで保たれ,タンパク質ファミリー間の安定性の正確な予測を可能にします.
結論:
- ヒトのタンパク質の多様性を測定することは可能である.
- 生成されたデータセットは,臨床的変異の解釈にとって貴重な参考となる.
- 発見は,変数効果を予測するための計算方法の開発とベンチマークをサポートします.
さらに関連する動画
11:49A Novel Saturation Mutagenesis Approach: Single Step Characterization of Regulatory Protein Binding Sites in RNA Using Phosphorothioates
Published on: August 21, 2018
6.5K
09:01Mutagenesis and Functional Selection Protocols for Directed Evolution of Proteins in E. coli
Published on: March 16, 2011
30.4K
関連する概念動画
02:26Conservation of Protein Domains Over Different Proteins
10.8K
Protein domains are small structurally independent units that are part of a single amino acid chain. Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
10.8K
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
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
02:26Conservation of Protein Domains
3.1K
3.1K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
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