Effects of Nf2 Missense Mutations on Schwannomin Interactions

• Published in: Biochemical and biophysical research communications 2002-01, Vol.290 (1), p.366-374
• Main Authors: Scoles, Daniel R., Chen, Mercy, Pulst, Stefan-M.
• Format: Article
• Language: English
• Subjects: Brain Neoplasms - metabolism; Codon, Nonsense; DNA, Complementary - metabolism; Genes, Neurofibromatosis 2; Germ-Line Mutation; Hrs; Humans; merlin; missense; Models, Genetic; Mutagenesis, Site-Directed; Mutation; Mutation, Missense; neurofibromatosis; Neurofibromin 2 - chemistry; Neurofibromin 2 - metabolism; NF2; Nf2 gene; p110; Phosphatidylinositol 3-Kinases - genetics; Plasmids - metabolism; Polymerase Chain Reaction; Protein Binding; Protein Conformation; Protein Folding; Protein Isoforms; Protein Structure, Tertiary; schwannomin; Spectrin - chemistry; Two-Hybrid System Techniques; βII-spectrin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2001.6178

Most benign brain tumors are associated with loss of the Nf2 gene tumor suppressor product schwannomin/merlin. Interactions between schwannomin fragments have given rise to hypotheses of in vivo schwannomin folding and dimerization. Previously, we showed that schwannomin with missense mutations L360P, L535P, and Q538P alters interaction with βII-spectrin and Hrs. Using yeast two-hybrid tests of interaction, we now show the effects of 11 Nf2 missense mutations on schwannomin self-interaction as well as schwannomin interaction with Hrs isoforms 1 and 2, βII-spectrin, and p110. Missense mutations L46R and K364I significantly decreased affinity of schwannomin for binding all interacting proteins. The schwannomin L46R mutation may result in a complex conformational change that alters folding and denies βII-spectrin access to an intact binding site in the C-terminal half of schwannomin. We show that unique inter- and intramolecular interactions occur for schwannomin isoform 2, suggesting that this schwannomin isoform has unique functional properties compared to schwannomin isoform 1.