腫瘍死滅因子αの活動は,ダイナミックな形状的再配置によって調節される.
Daniela Hofmann1, Loïc Salmon1, Gerhard Wider1
1Institute of Molecular Biology and Biophysics, ETH Zürich , 8093 Zürich, Switzerland.
Journal of the American Chemical Society
|December 2, 2017
まとめ
腫瘍死因α (TNFα) の不活性化は,NMRを用いて研究された. TNFαインターフェースを混乱させると 炎症性疾患を標的とする新しい戦略が生まれます
科学分野:
- 生物化学
- 免疫学
- 構造生物学
背景:
- 腫瘍死因α (TNFα) は,免疫反応を調節する重要なサイトカインです.
- 主要な慢性炎症疾患に 関わっている.
- タンパク質とタンパク質のインターフェースを妨害することによってTNFαを非活性化することは治療戦略ですが,そのメカニズムは不明です.
研究 の 目的:
- TNFα不活性化の原子解像度メカニズムを解明する.
- 活性型と非活性型TNFαの溶液構造とダイナミクスを研究する.
- インタフェースの乱れがTNFαの構成と動態にどのように影響するかを理解する.
主な方法:
- 溶液の構造とダイナミクスを調べるための核磁気共振 (NMR) スペクトロスコーピー.
- トリメリゼーション界面での残基のサイト指向型変異.
- 低分子量阻害剤でTNFαインターフェースを標的とする.
主要な成果:
- TNFαは様々な時間スケールの動きを示します.
- TNFαインターフェースの混乱は,その全体的な構造やトリメア状態を変化させなかった.
- 不活性化により,インターフェースから受容体結合領域への構造動態が増加した.
結論:
- TNFα不活性化には完全な構造崩壊ではなく,構造動態の増大が伴う.
- これらの発見は,TNFα不活性化に関するメカニズム的な洞察を提供します.
- この研究は,炎症性疾患におけるTNFα活性を標的とする新しい戦略を開発するための基礎を築いています.
さらに関連する動画
16:07Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody mAb by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
9.7K
08:19Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
6.5K
関連する概念動画
TGF - β Signaling Pathway
10.6K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.6K
NF-κB-dependent Signaling Pathway
10.1K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
10.1K
Enzyme-linked Receptors
86.8K
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
86.8K
Bacterial Protein Maturation
595
Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
595
Protein Folding
11.7K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
11.7K
Tail-anchoring of Proteins in the ER Membrane
3.9K
Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
3.9K
