ジャーナル: Commun Biol / 年: 2021 タイトル: Conformational distortion in a fibril-forming oligomer arrests alpha-Synuclein fibrillation and minimizes its toxic effects. 著者: Ritobrita Chakraborty / Sandip Dey / Pallabi Sil / Simanta Sarani Paul / Dipita Bhattacharyya / Anirban Bhunia / Jayati Sengupta / Krishnananda Chattopadhyay / 要旨: The fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson's disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity ...The fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson's disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity are not yet understood. We report that the addition of the physiologically-available small molecule heme at a sub-stoichiometric ratio to either monomeric or aggregated α-Syn, targets a His50 residue critical for fibril-formation and stabilizes the structurally-heterogeneous populations of aggregates into a minimally-toxic oligomeric state. Cryo-EM 3D reconstruction revealed a 'mace'-shaped structure of this monodisperse population of oligomers, which is comparable to a solid-state NMR Greek key-like motif (where the core residues are arranged in parallel in-register sheets with a Greek key topology at the C terminus) that forms the fundamental unit/kernel of protofilaments. Further structural analyses suggest that heme binding induces a distortion in the Greek key-like architecture of the mace oligomers, which impairs their further appending into protofilaments and fibrils. Additionally, our study reports a novel mechanism of prevention as well as reclamation of amyloid fibril formation by blocking an inter-protofilament His50 residue using a small molecule.
ダウンロード / ファイル: emd_31004.map.gz / 形式: CCP4 / 大きさ: 1.4 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈
It is a cryo-EM map of alfa-syneuclein tetramer in presence of heme. alfa-syneuclein monomer was incubated with heme molecule to prepare the sample.
ボクセルのサイズ
X=Y=Z: 1.89 Å
密度
表面レベル
登録者による: 8.0 / ムービー #1: 10
最小 - 最大
-17.406523 - 43.313667
平均 (標準偏差)
0.7616836 (±4.508148)
対称性
空間群: 1
詳細
EMDB XML:
マップ形状
Axis order
X
Y
Z
Origin
0
0
0
サイズ
72
72
72
Spacing
72
72
72
セル
A=B=C: 136.08 Å α=β=γ: 90.0 °
CCP4マップ ヘッダ情報:
mode
Image stored as Reals
Å/pix. X/Y/Z
1.89
1.89
1.89
M x/y/z
72
72
72
origin x/y/z
0.000
0.000
0.000
length x/y/z
136.080
136.080
136.080
α/β/γ
90.000
90.000
90.000
start NX/NY/NZ
0
0
0
NX/NY/NZ
256
256
256
MAP C/R/S
1
2
3
start NC/NR/NS
0
0
0
NC/NR/NS
72
72
72
D min/max/mean
-17.407
43.314
0.762
-
添付データ
-
試料の構成要素
-
全体 : Heme arrested off-pathway oligomer of alfa-syneuclein
全体
名称: Heme arrested off-pathway oligomer of alfa-syneuclein
要素
複合体: Heme arrested off-pathway oligomer of alfa-syneuclein
-
超分子 #1: Heme arrested off-pathway oligomer of alfa-syneuclein
超分子
名称: Heme arrested off-pathway oligomer of alfa-syneuclein タイプ: complex / ID: 1 / 親要素: 0 詳細: To generate off-pathway oligomer, alfa-syneuclein was incubated with heme in shaking (120 rpm)condition for 22 hrs at 37C.