Structural basis of activation of the tumor suppressor protein neurofibromin

Chaker-Margot, Malik and Werten, Sebastiaan and Dunzendorfer-Matt, Theresia and Lechner, Stefan and Ruepp, Angela and Scheffzek, Klaus and Maier, Timm. (2022) Structural basis of activation of the tumor suppressor protein neurofibromin. Molecular Cell, 82 (7). pp. 1288-1296.e5.

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Official URL: https://edoc.unibas.ch/88505/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:07 Jun 2022 10:40
Deposited On:07 Jun 2022 10:40

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