7R03

Neurofibromin occluded conformation

Summary for 7R03

• Entry DOI: 10.2210/pdb7r03/pdb
• Related: 7R04
• EMDB information: 14218
• Descriptor: Isoform I of Neurofibromin (1 entity in total)
• Functional Keywords: signalling protein, gap, neurofibromatosis type i, homodimer, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 634821.62

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

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: 35353986
DOI: 10.1016/j.molcel.2022.03.011

Experimental method

ELECTRON MICROSCOPY (3.6 Å)