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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments | |||||||||
![]() | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. | |||||||||
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![]() | amyloid-like fibril / SIGNALING PROTEIN | |||||||||
機能・相同性 | ![]() negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / acute-phase response / Regulation of insulin secretion / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin-like growth factor receptor binding / insulin receptor binding / wound healing / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / regulation of protein localization / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.2 Å | |||||||||
![]() | Wang LW / Hall C / Uchikawa E / Chen DL / Choi E / Zhang XW / Bai XC | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis of insulin fibrillation. 著者: Liwei Wang / Catherine E Hall / Emiko Uchikawa / Dailu Chen / Eunhee Choi / Xuewu Zhang / Xiao-Chen Bai / ![]() 要旨: Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and ...Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes. | |||||||||
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マップデータ | ![]() | 2.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 17.2 KB 17.2 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 7.4 KB | 表示 | ![]() |
画像 | ![]() | 27.4 KB | ||
その他 | ![]() ![]() | 25.6 MB 25.5 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8sbdMC M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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注釈 | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.83 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: Cryo-EM structure of insulin amyloid-like fibril that is...
ファイル | emd_40305_half_map_1.map | ||||||||||||
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注釈 | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. Half map 1. | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Cryo-EM structure of insulin amyloid-like fibril that is...
ファイル | emd_40305_half_map_2.map | ||||||||||||
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注釈 | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. Half map 2. | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : Cryo-EM structure of insulin amyloid-like fibril that is composed...
全体 | 名称: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments |
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要素 |
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-超分子 #1: Cryo-EM structure of insulin amyloid-like fibril that is composed...
超分子 | 名称: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: ![]() |
-分子 #1: Insulin B chain
分子 | 名称: Insulin B chain / タイプ: protein_or_peptide / ID: 1 / コピー数: 16 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 3.433953 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: FVNQHLCGSH LVEALYLVCG ERGFFYTPKT UniProtKB: Insulin |
-分子 #2: Insulin A chain
分子 | 名称: Insulin A chain / タイプ: protein_or_peptide / ID: 2 / コピー数: 16 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 2.383698 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GIVEQCCTSI CSLYQLENYC N UniProtKB: Insulin |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | filament |
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試料調製
濃度 | 1 mg/mL |
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緩衝液 | pH: 2 |
グリッド | モデル: Quantifoil R1.2/1.3 / 材質: GOLD / メッシュ: 300 |
凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum / エネルギーフィルター - スリット幅: 20 eV |
撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 撮影したグリッド数: 1 / 平均露光時間: 8.0 sec. / 平均電子線量: 60.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.6 µm / 最小 デフォーカス(公称値): 1.6 µm |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
-原子モデル構築 1
精密化 | 空間: REAL / プロトコル: FLEXIBLE FIT |
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得られたモデル | ![]() PDB-8sbd: |