EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation.
ジャーナル・号・ページ	Elife, Vol. 12, Year 2024
掲載日	2024年8月28日
著者	Lukas Frey / Dhiman Ghosh / Bilal M Qureshi / David Rhyner / Ricardo Guerrero-Ferreira / Aditya Pokharna / Witek Kwiatkowski / Tetiana Serdiuk / Paola Picotti / Roland Riek / Jason Greenwald /
PubMed 要旨	The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical ...The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.
リンク	Elife / PubMed:39196271 / PubMed Central
手法	EM (らせん対称)
解像度	2.23 - 3.41 Å
構造データ	17693 8pix EMDB-17693, PDB-8pix: Cryo EM structure of the type 3C polymorph of alpha-synuclein at low pH. 手法: EM (らせん対称) / 解像度: 3.41 Å 17714 8pjo EMDB-17714, PDB-8pjo: Cryo EM structure of the type 3D polymorph of alpha-synuclein E46K mutant at low pH. 手法: EM (らせん対称) / 解像度: 2.31 Å 17723 8pk2 EMDB-17723, PDB-8pk2: Cryo EM structure of the type 1m polymorph of alpha-synuclein 手法: EM (らせん対称) / 解像度: 3.26 Å 17726 8pk4 EMDB-17726, PDB-8pk4: Cryo EM structure of the type 5A polymorph of alpha-synuclein. 手法: EM (らせん対称) / 解像度: 3.3 Å EMDB-50077: Cryo EM map of the type 2B polymorph of alpha-synuclein at pH 7.0. 手法: EM (らせん対称) / 解像度: 2.95 Å EMDB-50860: Cryo EM map of the type 2A polymorph of alpha-synuclein at pH 7.0. 手法: EM (らせん対称) / 解像度: 2.86 Å 50888 9fyp EMDB-50888, PDB-9fyp: Cryo EM structure of the type 3B polymorph of alpha-synuclein at low pH. 手法: EM (らせん対称) / 解像度: 2.23 Å
化合物	ChemComp-CL: Unknown entry / クロリド ChemComp-HOH: WATER
由来	homo sapiens (ヒト)
キーワード	PROTEIN FIBRIL / amyloid / polymorphism