{"entity": "researcher", "timestamp": "2026-06-18T14:46:43.929Z", "family": "Rupp", "given": "Bernhard", "initials": "B", "orcid": "0000-0002-3300-6965", "affiliations": [], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/fe0f75c058924439946979522422acfc.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/fe0f75c058924439946979522422acfc"}}, "publications": [{"entity": "publication", "iuid": "d115ad4696a443b0b421db0cdfd1f465", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d115ad4696a443b0b421db0cdfd1f465.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d115ad4696a443b0b421db0cdfd1f465"}}, "title": "The structure of neurofibromin isoform 2 reveals different functional states.", "authors": [{"family": "Naschberger", "given": "Andreas", "initials": "A"}, {"family": "Baradaran", "given": "Rozbeh", "initials": "R", "orcid": "0000-0002-6096-9169", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af7262546e54fc3a36f3bac03e15a79.json"}}, {"family": "Rupp", "given": "Bernhard", "initials": "B", "orcid": "0000-0002-3300-6965", "researcher": {"href": "https://publications.scilifelab.se/researcher/fe0f75c058924439946979522422acfc.json"}}, {"family": "Carroni", "given": "Marta", "initials": "M", "orcid": "0000-0002-7697-6427", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7f1bc1767024368abcb11a83184994a.json"}}], "type": "journal article", "published": "2021-10-27", "journal": {"title": "Nature", "issn": "1476-4687", "issn-l": "0028-0836", "volume": null, "issue": null, "pages": null}, "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)1,2. 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 \u00c5. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing3 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 membrane4. 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.", "doi": "10.1038/s41586-021-04024-x", "pmid": "34707296", "labels": {"Cryo-EM": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41586-021-04024-x"}], "notes": [], "created": "2021-11-03T13:45:56.999Z", "modified": "2021-11-10T12:21:33.839Z"}]}