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-Structure paper
タイトル | The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 28, Issue 12, Page 982-988, Year 2021 |
掲載日 | 2021年12月9日 |
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 / |
PubMed 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. |
リンク | Nat Struct Mol Biol / PubMed:34887559 |
手法 | EM (単粒子) |
解像度 | 4.56 - 6.25 Å |
構造データ | EMDB-23924, PDB-7moc: EMDB-23929, PDB-7mp5: EMDB-23930, PDB-7mp6: |
由来 |
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キーワード | ANTITUMOR PROTEIN / Scaffold / RAS-GAP / HEAT repeat / Autoinhibition / tumour suppressor / tumor supressor |