7MP6

Neurofibromin homodimer

7MP6 の概要

• エントリーDOI: 10.2210/pdb7mp6/pdb
• EMDBエントリー: 23924 23929 23930
• 分子名称: Isoform I of Neurofibromin (1 entity in total)
• 機能のキーワード: tumor supressor, heat repeat, ras-gap, scaffold, antitumor protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 636815.62

構造登録者

Lupton, C.J.,Bayly-Jones, C.,Ellisdon, A.M. (登録日: 2021-05-04, 公開日: 2021-12-15, 最終更新日: 2024-05-29)

主引用文献

Lupton, C.J.,Bayly-Jones, C.,D'Andrea, L.,Huang, C.,Schittenhelm, R.B.,Venugopal, H.,Whisstock, J.C.,Halls, M.L.,Ellisdon, A.M.
The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1.
Nat.Struct.Mol.Biol., 28:982-988, 2021

PubMed Abstract: 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.

PubMed: 34887559
DOI: 10.1038/s41594-021-00687-2

実験手法

ELECTRON MICROSCOPY (6.25 Å)