7PGP

The core structure of human neurofibromin isoform 2

7PGP の概要

• エントリーDOI: 10.2210/pdb7pgp/pdb
• EMDBエントリー: 13391
• 分子名称: Neurofibromin (1 entity in total)
• 機能のキーワード: neurofibromin, cancer, gap, ras, neurofibromatosis type 1, signaling 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: 639515.31

構造登録者

Naschberger, A.,Baradaran, R.,Carroni, M.,Rupp, B. (登録日: 2021-08-15, 公開日: 2022-08-24, 最終更新日: 2024-07-17)

主引用文献

Naschberger, A.,Baradaran, R.,Rupp, B.,Carroni, M.
The structure of neurofibromin isoform 2 reveals different functional states.
Nature, 599:315-319, 2021

PubMed Abstract: The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1). As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3 Å. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane. Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis.

PubMed: 34707296
DOI: 10.1038/s41586-021-04024-x

実験手法

ELECTRON MICROSCOPY (3.1 Å)