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Structure paper

TitleThe structure of neurofibromin isoform 2 reveals different functional states.
Journal, issue, pagesNature, Vol. 599, Issue 7884, Page 315-319, Year 2021
Publish dateOct 27, 2021
AuthorsAndreas Naschberger / Rozbeh Baradaran / Bernhard Rupp / Marta Carroni /
PubMed AbstractThe 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 ...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.
External linksNature / PubMed:34707296 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 4.8 Å
Structure data

EMDB-13391, PDB-7pgp:
The core structure of human neurofibromin isoform 2
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-13392, PDB-7pgq:
GAP-SecPH region of human neurofibromin isoform 2 in closed conformation.
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-13393, PDB-7pgr:
The structure of human neurofibromin isoform 2 in closed conformation
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-13394, PDB-7pgs:
Consensus structure of human Neurofibromin isoform 2
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-13395, PDB-7pgt:
The structure of human neurofibromin isoform 2 in opened conformation.
Method: EM (single particle) / Resolution: 4.8 Å

EMDB-13396, PDB-7pgu:
Autoinhibited structure of human neurofibromin isoform 2 stabilized by Zinc.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-13397:
The tip region of human Neurofibromin Isoform 2 stabilized by Zinc
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-13398:
The core region of human Neurofibromin Isoform 2 stabilized by Zinc.
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-13399:
The GAP-SecPH region of human Neurofibromin Isoform 2 stabilized by Zinc.
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-PEV:
(1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / POPE, phospholipid*YM

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Neurofibromin / Cancer / GAP / Ras / Neurofibromatosis type 1

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