7R04
Neurofibromin in open conformation
Summary for 7R04
| Entry DOI | 10.2210/pdb7r04/pdb |
| Related | 7R03 |
| EMDB information | 14219 |
| Descriptor | Isoform I of Neurofibromin, 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE (2 entities in total) |
| Functional Keywords | signalling protein, homodimer, neurofibromatosis, gap, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 635360.87 |
| Authors | Chaker-Margot, M.,Scheffzek, K.,Maier, T. (deposition date: 2022-02-01, release date: 2022-03-30, Last modification date: 2024-07-17) |
| Primary citation | Chaker-Margot, M.,Werten, S.,Dunzendorfer-Matt, T.,Lechner, S.,Ruepp, A.,Scheffzek, K.,Maier, T. Structural basis of activation of the tumor suppressor protein neurofibromin. Mol.Cell, 82:1288-, 2022 Cited by 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 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. PubMed: 35353986DOI: 10.1016/j.molcel.2022.03.011 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.7 Å) |
Structure validation
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