+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7moc | ||||||
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タイトル | Neurofibromin core | ||||||
要素 | Isoform I of Neurofibromin | ||||||
キーワード | ANTITUMOR PROTEIN / Scaffold / RAS-GAP / HEAT repeat / Autoinhibition | ||||||
機能・相同性 | 機能・相同性情報 positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / mast cell proliferation / amygdala development / mast cell apoptotic process ...positive regulation of mast cell apoptotic process / negative regulation of Rac protein signal transduction / regulation of glial cell differentiation / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / mast cell proliferation / amygdala development / mast cell apoptotic process / negative regulation of mast cell proliferation / gamma-aminobutyric acid secretion, neurotransmission / Schwann cell proliferation / vascular associated smooth muscle cell proliferation / glutamate secretion, neurotransmission / negative regulation of Schwann cell proliferation / negative regulation of leukocyte migration / negative regulation of neurotransmitter secretion / negative regulation of vascular associated smooth muscle cell migration / positive regulation of adenylate cyclase activity / forebrain morphogenesis / hair follicle maturation / regulation of cell-matrix adhesion / regulation of blood vessel endothelial cell migration / smooth muscle tissue development / camera-type eye morphogenesis / cell communication / negative regulation of oligodendrocyte differentiation / peripheral nervous system development / myelination in peripheral nervous system / phosphatidylcholine binding / sympathetic nervous system development / myeloid leukocyte migration / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / metanephros development / negative regulation of Ras protein signal transduction / phosphatidylethanolamine binding / collagen fibril organization / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / endothelial cell proliferation / forebrain astrocyte development / artery morphogenesis / pigmentation / regulation of postsynapse organization / regulation of GTPase activity / negative regulation of neuroblast proliferation / adrenal gland development / negative regulation of protein import into nucleus / regulation of synaptic transmission, GABAergic / negative regulation of cell-matrix adhesion / spinal cord development / Rac protein signal transduction / negative regulation of osteoclast differentiation / negative regulation of endothelial cell proliferation / oligodendrocyte differentiation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / extrinsic apoptotic signaling pathway via death domain receptors / neuroblast proliferation / negative regulation of MAPK cascade / regulation of angiogenesis / Schwann cell development / negative regulation of stem cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of fibroblast proliferation / skeletal muscle tissue development / negative regulation of MAP kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade / GTPase activator activity / extracellular matrix organization / negative regulation of angiogenesis / osteoclast differentiation / liver development / positive regulation of GTPase activity / negative regulation of cell migration / stem cell proliferation / cognition / long-term synaptic potentiation / negative regulation of protein kinase activity / brain development / wound healing / regulation of long-term neuronal synaptic plasticity / visual learning / cerebral cortex development / osteoblast differentiation / Regulation of RAS by GAPs / protein import into nucleus / positive regulation of neuron apoptotic process / MAPK cascade / heart development / presynapse / cellular response to heat / actin cytoskeleton organization / fibroblast proliferation / regulation of gene expression 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.56 Å | ||||||
データ登録者 | Lupton, C.J. / Bayly-Jones, C. / Ellisdon, A.M. | ||||||
資金援助 | 1件
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引用 | ジャーナル: Nat Struct Mol Biol / 年: 2021 タイトル: The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. 著者: Christopher J Lupton / Charles Bayly-Jones / Laura D'Andrea / Cheng Huang / Ralf B Schittenhelm / Hari Venugopal / James C Whisstock / Michelle L Halls / Andrew M Ellisdon / 要旨: Neurofibromin (NF1) mutations cause neurofibromatosis type 1 and drive numerous cancers, including breast and brain tumors. NF1 inhibits cellular proliferation through its guanosine triphosphatase- ...Neurofibromin (NF1) mutations cause neurofibromatosis type 1 and drive numerous cancers, including breast and brain tumors. NF1 inhibits cellular proliferation through its guanosine triphosphatase-activating protein (GAP) activity against rat sarcoma (RAS). In the present study, cryo-electron microscope studies reveal that the human ~640-kDa NF1 homodimer features a gigantic 30 × 10 nm array of α-helices that form a core lemniscate-shaped scaffold. Three-dimensional variability analysis captured the catalytic GAP-related domain and lipid-binding SEC-PH domains positioned against the core scaffold in a closed, autoinhibited conformation. We postulate that interaction with the plasma membrane may release the closed conformation to promote RAS inactivation. Our structural data further allow us to map the location of disease-associated NF1 variants and provide a long-sought-after structural explanation for the extreme susceptibility of the molecule to loss-of-function mutations. Collectively these findings present potential new routes for therapeutic modulation of the RAS pathway. | ||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7moc.cif.gz | 380.6 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7moc.ent.gz | 264.4 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7moc.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7moc_validation.pdf.gz | 1.3 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7moc_full_validation.pdf.gz | 1.3 MB | 表示 | |
XML形式データ | 7moc_validation.xml.gz | 55.6 KB | 表示 | |
CIF形式データ | 7moc_validation.cif.gz | 85.8 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/mo/7moc ftp://data.pdbj.org/pub/pdb/validation_reports/mo/7moc | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
#1: タンパク質 | 分子量: 318407.812 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: NF1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P21359 |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: Neurofibromin / タイプ: COMPLEX / 詳細: A single lobe of the neurofibromin dimer / Entity ID: all / 由来: RECOMBINANT |
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分子量 | 値: 0.636 MDa / 実験値: YES |
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
緩衝液 | pH: 8 |
試料 | 濃度: 0.4 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 200 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 |
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Talos Arctica / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TALOS ARCTICA |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / アライメント法: COMA FREE |
撮影 | 電子線照射量: 40 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: FEI FALCON III (4k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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対称性 | 点対称性: C1 (非対称) |
3次元再構成 | 解像度: 4.56 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 34933 / 対称性のタイプ: POINT |