8E20

Cryo-EM structure of the full-length human NF1 dimer

Summary for 8E20

• Entry DOI: 10.2210/pdb8e20/pdb
• EMDB information: 27826
• Descriptor: Isoform I of Neurofibromin (1 entity in total)
• Functional Keywords: gtpase activating protein, ras signaling, cancer, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 634821.62

Authors

Darling, J.E.,Merk, A.,Grisshammer, R.,Ognjenovic, J. (deposition date: 2022-08-12, release date: 2023-04-26, Last modification date: 2025-05-28)

Primary citation

Young, L.C.,Goldstein de Salazar, R.,Han, S.W.,Huang, Z.Y.S.,Merk, A.,Drew, M.,Darling, J.,Wall, V.,Grisshammer, R.,Cheng, A.,Allison, M.R.,Sale, M.J.,Nissley, D.V.,Esposito, D.,Ognjenovic, J.,McCormick, F.
Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
Proc.Natl.Acad.Sci.USA, 120:e2208960120-e2208960120, 2023

PubMed Abstract: The majority of pathogenic mutations in the neurofibromatosis type I () gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.

PubMed: 36689660
DOI: 10.1073/pnas.2208960120

Experimental method

ELECTRON MICROSCOPY (3.6 Å)