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TitleStructural basis of activation of the tumor suppressor protein neurofibromin.
Journal, issue, pagesMol Cell, Vol. 82, Issue 7, Page 1288-11296.e5, Year 2022
Publish dateApr 7, 2022
AuthorsMalik Chaker-Margot / Sebastiaan Werten / Theresia Dunzendorfer-Matt / Stefan Lechner / Angela Ruepp / Klaus Scheffzek / Timm Maier /
PubMed AbstractMutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and ...Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and acts as a tumor suppressor by negatively regulating the small GTPase, Ras. However, structural insights into neurofibromin activation remain incompletely defined. Here, we provide cryoelectron microscopy (cryo-EM) structures that reveal an extended neurofibromin homodimer in two functional states: an auto-inhibited state with occluded Ras-binding site and an asymmetric open state with an exposed Ras-binding site. Mechanistically, the transition to the active conformation is stimulated by nucleotide binding, which releases a lock that tethers the catalytic domain to an extended helical repeat scaffold in the occluded state. Structure-guided mutational analysis supports functional relevance of allosteric control. Disease-causing mutations are mapped and primarily impact neurofibromin stability. Our findings suggest a role for nucleotides in neurofibromin regulation and may lead to therapeutic modulation of Ras signaling.
External linksMol Cell / PubMed:35353986
MethodsEM (single particle)
Resolution3.6 - 3.7 Å
Structure data

14218

7r03

EMDB-14218: Composite map of the occluded conformation of neurofibromin
PDB-7r03: Neurofibromin occluded conformation
Method: EM (single particle) / Resolution: 3.6 Å

14219

7r04

EMDB-14219: Composite map of the open conformation of neurofibromin
PDB-7r04: Neurofibromin in open conformation
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Signalling protein / GAP / Neurofibromatosis type I / Homodimer / Neurofibromatosis

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