AT8,AT100,PHF1のエピトープにおけるプロリン誘導型擬酸化が441の残留タウに及ぼす構造的影響
Stefan Bibow1, Valéry Ozenne, Jacek Biernat
1Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Journal of the American Chemical Society
|September 14, 2011
まとめ
アルツハイマー病の重要な要因であるタウタンパク質の偽酸化により,その構造が開く. この発見は,本質的に無秩序なタンパク質における一時的な相互作用を調節することが,結合を防ぐために重要であることを示唆しています.
科学分野:
- 神経科学は神経科学である.
- 構造生物学 構造生物学とは
- バイオケミストリー バイオケミストリー
背景:
- タウのような内在的に乱れたタンパク質は,神経変性疾患に関与しています.
- タウタンパク質の高酸化と神経線維細胞の絡み合いが,アルツハイマー病の特徴である.
研究 の 目的:
- タウタンパク質のリン酸化による構造的効果を調査する.
- フォスフォリレーションの模倣がタウの形状にどのように影響するかを理解するために.
主な方法:
- リン酸化部位 (AT8,AT100,PHF1) を模倣するグルタミン酸置換による変異性タウタンパク質の特徴化.
- NMRパラマグネティック・リラクゼーション・エンハンスメント (PRE) を利用し,距離制限を集めた.
- タンパク質の構造を分析するためにアンサンブルコンフォマー計算を使用した.
主要な成果:
- 偽リン酸化は,タウの一時的な折りたたみ構造の重要な"開き"を誘導した.
- NMR PREデータは,構造分析のための広範な距離制限を提供しました.
- アンサンブル計算では,突然変異による形状の変化が明らかになった.
結論:
- グルタミン酸変異によるタウリン酸化を模倣することで,その原生構造が変化します.
- 暫定的な長距離相互作用は,本質的に乱れたタンパク質の共通の特徴である.
- これらの相互作用の調節は,アルツハイマー病などの疾患に関連するタンパク質の集積に不可欠です.
関連する概念動画
01:02Phosphorylation
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...
02:54Protein Kinases and Phosphatases
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...
02:04Covalently Linked Protein Regulators
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.
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...