The autosomal dominant monogenetic disease neurofibromato sis type 1(NF1)affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene,leading to dysfunction in the protein neurofibromin(Nf1)1,2.As a GTPase-activating protein,a key function of Nf1 is repression of the Ras oncogene signalling cascade.We determined the human Nf1 dimer structure at an overall resolution of 3.3 A.The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing3 isoform 2 in a closed,self-inhibited,Zn-stabilized state and an open state.In the closed conformation,HEAT/ARM core domains shield the GTPase-activating protein-related domain(GRD)so that Ras binding is sterically inhibited.In a distinctly different.
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