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Title | Structural basis of activation of the tumor suppressor protein neurofibromin. |
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Journal, issue, pages | Mol Cell, Vol. 82, Issue 7, Page 1288-11296.e5, Year 2022 |
Publish date | Apr 7, 2022 |
Authors | Malik Chaker-Margot / Sebastiaan Werten / Theresia Dunzendorfer-Matt / Stefan Lechner / Angela Ruepp / Klaus Scheffzek / Timm Maier / |
PubMed Abstract | 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 ...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 links | Mol Cell / PubMed:35353986 |
Methods | EM (single particle) |
Resolution | 3.6 - 3.7 Å |
Structure data | EMDB-14218: Composite map of the occluded conformation of neurofibromin EMDB-14219: Composite map of the open conformation of neurofibromin |
Chemicals | ChemComp-GSP: |
Source |
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Keywords | SIGNALING PROTEIN / Signalling protein / GAP / Neurofibromatosis type I / Homodimer / Neurofibromatosis |