7PGQ
GAP-SecPH region of human neurofibromin isoform 2 in closed conformation.
Summary for 7PGQ
| Entry DOI | 10.2210/pdb7pgq/pdb |
| EMDB information | 13392 |
| Descriptor | Neurofibromin, (1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE, ZINC ION (3 entities in total) |
| Functional Keywords | neurofibromin, cancer, gap, ras, neurofibromatosis type 1, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 640300.73 |
| Authors | Naschberger, A.,Baradaran, R.,Carroni, M.,Rupp, B. (deposition date: 2021-08-15, release date: 2022-10-26, Last modification date: 2024-07-17) |
| Primary citation | Naschberger, A.,Baradaran, R.,Rupp, B.,Carroni, M. The structure of neurofibromin isoform 2 reveals different functional states. Nature, 599:315-319, 2021 Cited by 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: 34707296DOI: 10.1038/s41586-021-04024-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.5 Å) |
Structure validation
Download full validation report
