+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-23929 | |||||||||
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タイトル | Autoinhibited neurofibrobmin | |||||||||
マップデータ | ||||||||||
試料 |
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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 / gamma-aminobutyric acid secretion, neurotransmission / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / 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 / gamma-aminobutyric acid secretion, neurotransmission / observational learning / Schwann cell migration / negative regulation of Schwann cell migration / vascular associated smooth muscle cell migration / amygdala development / mast cell apoptotic process / negative regulation of mast cell proliferation / Schwann cell proliferation / vascular associated smooth muscle cell proliferation / mast cell proliferation / glutamate secretion, neurotransmission / negative regulation of Schwann cell proliferation / negative regulation of leukocyte migration / negative regulation of vascular associated smooth muscle cell migration / positive regulation of adenylate cyclase activity / regulation of cell-matrix adhesion / forebrain morphogenesis / negative regulation of neurotransmitter secretion / hair follicle maturation / regulation of blood vessel endothelial cell migration / cell communication / smooth muscle tissue development / camera-type eye morphogenesis / negative regulation of oligodendrocyte differentiation / sympathetic nervous system development / myelination in peripheral nervous system / myeloid leukocyte migration / phosphatidylcholine binding / phosphatidylethanolamine binding / peripheral nervous system development / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / collagen fibril organization / endothelial cell proliferation / regulation of bone resorption / regulation of long-term synaptic potentiation / neural tube development / regulation of postsynapse organization / forebrain astrocyte development / 顔料 / artery morphogenesis / negative regulation of neuroblast proliferation / regulation of synaptic transmission, GABAergic / adrenal gland development / negative regulation of protein import into nucleus / negative regulation of cell-matrix adhesion / spinal cord development / regulation of GTPase activity / negative regulation of MAPK cascade / Rac protein signal transduction / oligodendrocyte differentiation / negative regulation of osteoclast differentiation / negative regulation of endothelial cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of astrocyte differentiation / neuroblast proliferation / extrinsic apoptotic signaling pathway via death domain receptors / regulation of angiogenesis / Schwann cell development / negative regulation of stem cell proliferation / negative regulation of fibroblast proliferation / skeletal muscle tissue development / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / GTPase activator activity / extracellular matrix organization / negative regulation of angiogenesis / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / negative regulation of cell migration / liver development / negative regulation of MAP kinase activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / long-term synaptic potentiation / stem cell proliferation / regulation of long-term neuronal synaptic plasticity / brain development / negative regulation of protein kinase activity / visual learning / wound healing / cerebral cortex development / 認識 / positive regulation of GTPase activity / osteoblast differentiation / protein import into nucleus / Regulation of RAS by GAPs / positive regulation of neuron apoptotic process / 分裂促進因子活性化タンパク質キナーゼ / presynapse / cellular response to heat / heart development / fibroblast proliferation / actin cytoskeleton organization / 遺伝子発現の調節 / 血管新生 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 5.6 Å | |||||||||
データ登録者 | Lupton CJ / Bayly-Jones C / Ellisdon AM | |||||||||
資金援助 | オーストラリア, 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 | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_23929.map.gz | 31.9 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-23929-v30.xml emd-23929.xml | 19.3 KB 19.3 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_23929_fsc.xml | 9.5 KB | 表示 | FSCデータファイル |
画像 | emd_23929.png | 59.5 KB | ||
マスクデータ | emd_23929_msk_1.map | 64 MB | マスクマップ | |
その他 | emd_23929_additional_1.map.gz emd_23929_half_map_1.map.gz emd_23929_half_map_2.map.gz | 32.8 MB 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-23929 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23929 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_23929.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.194 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
ファイル | emd_23929_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Sharpened map
ファイル | emd_23929_additional_1.map | ||||||||||||
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注釈 | Sharpened map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_23929_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_23929_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : Neurofibromin
全体 | 名称: Neurofibromin |
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要素 |
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-超分子 #1: Neurofibromin
超分子 | 名称: Neurofibromin / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all / 詳細: Autoinhibited state of neurofibromin |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
分子量 | 実験値: 636 KDa |
-分子 #1: Isoform I of Neurofibromin
分子 | 名称: Isoform I of Neurofibromin / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 318.407812 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MDYKDDDDKA AHRPVEWVQA VVSRFDEQLP IKTGQQNTHT KVSTEHNKEC LINISKYKFS LVISGLTTIL KNVNNMRIFG EAAEKNLYL SQLIILDTLE KCLAGQPKDT MRLDETMLVK QLLPEICHFL HTCREGNQHA AELRNSASGV LFSLSCNNFN A VFSRISTR ...文字列: MDYKDDDDKA AHRPVEWVQA VVSRFDEQLP IKTGQQNTHT KVSTEHNKEC LINISKYKFS LVISGLTTIL KNVNNMRIFG EAAEKNLYL SQLIILDTLE KCLAGQPKDT MRLDETMLVK QLLPEICHFL HTCREGNQHA AELRNSASGV LFSLSCNNFN A VFSRISTR LQELTVCSED NVDVHDIELL QYINVDCAKL KRLLKETAFK FKALKKVAQL AVINSLEKAF WNWVENYPDE FT KLYQIPQ TDMAECAEKL FDLVDGFAES TKRKAAVWPL QIILLILCPE IIQDISKDVV DENNMNKKLF LDSLRKALAG HGG SRQLTE SAAIACVKLC KASTYINWED NSVIFLLVQS MVVDLKNLLF NPSKPFSRGS QPADVDLMID CLVSCFRISP HNNQ HFKIC LAQNSPSTFH YVLVNSLHRI ITNSALDWWP KIDAVYCHSV ELRNMFGETL HKAVQGCGAH PAIRMAPSLT FKEKV TSLK FKEKPTDLET RSYKYLLLSM VKLIHADPKL LLCNPRKQGP ETQGSTAELI TGLVQLVPQS HMPEIAQEAM EALLVL HQL DSIDLWNPDA PVETFWEISS QMLFYICKKL TSHQMLSSTE ILKWLREILI CRNKFLLKNK QADRSSCHFL LFYGVGC DI PSSGNTSQMS MDHEELLRTP GASLRKGKGN SSMDSAAGCS GTPPICRQAQ TKLEVALYMF LWNPDTEAVL VAMSCFRH L CEEADIRCGV DEVSVHNLLP NYNTFMEFAS VSNMMSTGRA ALQKRVMALL RRIEHPTAGN TEAWEDTHAK WEQATKLIL NYPKAKMEDG QAAESLHKTI VKRRMSHVSG GGSIDLSDTD SLQEWINMTG FLCALGGVCL QQRSNSGLAT YSPPMGPVSE RKGSMISVM SSEGNADTPV SKFMDRLLSL MVCNHEKVGL QIRTNVKDLV GLELSPALYP MLFNKLKNTI SKFFDSQGQV L LTDTNTQF VEQTIAIMKN LLDNHTEGSS EHLGQASIET MMLNLVRYVR VLGNMVHAIQ IKTKLCQLVE VMMARRDDLS FC QEMKFRN KMVEYLTDWV MGTSNQAADD DVKCLTRDLD QASMEAVVSL LAGLPLQPEE GDGVELMEAK SQLFLKYFTL FMN LLNDCS EVEDESAQTG GRKRGMSRRL ASLRHCTVLA MSNLLNANVD SGLMHSIGLG YHKDLQTRAT FMEVLTKILQ QGTE FDTLA ETVLADRFER LVELVTMMGD QGELPIAMAL ANVVPCSQWD ELARVLVTLF DSRHLLYQLL WNMFSKEVEL ADSMQ TLFR GNSLASKIMT FCFKVYGATY LQKLLDPLLR IVITSSDWQH VSFEVDPTRL EPSESLEENQ RNLLQMTEKF FHAIIS SSS EFPPQLRSVC HCLYQVVSQR FPQNSIGAVG SAMFLRFINP AIVSPYEAGI LDKKPPPRIE RGLKLMSKIL QSIANHV LF TKEEHMRPFN DFVKSNFDAA RRFFLDIASD CPTSDAVNHS LSFISDGNVL ALHRLLWNNQ EKIGQYLSSN RDHKAVGR R PFDKMATLLA YLGPPEHKPV ADTHWSSLNL TSSKFEEFMT RHQVHEKEEF KALKTLSIFY QAGTSKAGNP IFYYVARRF KTGQINGDLL IYHVLLTLKP YYAKPYEIVV DLTHTGPSNR FKTDFLSKWF VVFPGFAYDN VSAVYIYNCN SWVREYTKYH ERLLTGLKG SKRLVFIDCP GKLAEHIEHE QQKLPAATLA LEEDLKVFHN ALKLAHKDTK VSIKVGSTAV QVTSAERTKV L GQSVFLND IYYASEIEEI CLVDENQFTL TIANQGTPLT FMHQECEAIV QSIIHIRTRW ELSQPDSIPQ HTKIRPKDVP GT LLNIALL NLGSSDPSLR SAAYNLLCAL TCTFNLKIEG QLLETSGLCI PANNTLFIVS ISKTLAANEP HLTLEFLEEC ISG FSKSSI ELKHLCLEYM TPWLSNLVRF CKHNDDAKRQ RVTAILDKLI TMTINEKQMY PSIQAKIWGS LGQITDLLDV VLDS FIKTS ATGGLGSIKA EVMADTAVAL ASGNVKLVSS KVIGRMCKII DKTCLSPTPT LEQHLMWDDI AILARYMLML SFNNS LDVA AHLPYLFHVV TFLVATGPLS LRASTHGLVI NIIHSLCTCS QLHFSEETKQ VLRLSLTEFS LPKFYLLFGI SKVKSA AVI AFRSSYRDRS FSPGSYERET FALTSLETVT EALLEIMEAC MRDIPTCKWL DQWTELAQRF AFQYNPSLQP RALVVFG CI SKRVSHGQIK QIIRILSKAL ESCLKGPDTY NSQVLIEATV IALTKLQPLL NKDSPLHKAL FWVAVAVLQL DEVNLYSA G TALLEQNLHT LDSLRIFNDK SPEEVFMAIR NPLEWHCKQM DHFVGLNFNS NFNFALVGHL LKGYRHPSPA IVARTVRIL HTLLTLVNKH RNCDKFEVNT QSVAYLAALL TVSEEVRSRC SLKHRKSLLL TDISMENVPM DTYPIHHGDP SYRTLKETQP WSSPKGSEG YLAATYPTVG QTSPRARKSM SLDMGQPSQA NTKKLLGTRK SFDHLISDTK APKRQEMESG ITTPPKMRRV A ETDYEMET QRISSSQQHP HLRKVSVSES NVLLDEEVLT DPKIQALLLT VLATLVKYTT DEFDQRILYE YLAEASVVFP KV FPVVHNL LDSKINTLLS LCQDPNLLNP IHGIVQSVVY HEESPPQYQT SYLQSFGFNG LWRFAGPFSK QTQIPDYAEL IVK FLDALI DTYLPGIDEE TSEESLLTPT SPYPPALQSQ LSITANLNLS NSMTSLATSQ HSPGIDKENV ELSPTTGHCN SGRT RHGSA SQVQKQRSAG SFKRNSIKKI V |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 0.4 mg/mL |
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緩衝液 | pH: 8 |
グリッド | モデル: Quantifoil R1.2/1.3 / 材質: COPPER / メッシュ: 200 / 前処理 - タイプ: GLOW DISCHARGE |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TALOS ARCTICA |
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電子線 | 加速電圧: 200 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm |
撮影 | フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 平均電子線量: 40.0 e/Å2 |
実験機器 | モデル: Talos Arctica / 画像提供: FEI Company |