Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2.

Abstract

Neurofibromatosis type 2 (NF2) is a tumor-forming disease of the nervous system caused by deletion or by loss-of-function mutations in NF2, encoding the tumor suppressing protein neurofibromin 2 (also known as schwannomin or merlin). Neurofibromin 2 is a member of the ezrin, radixin, moesin (ERM) family of proteins regulating the cytoskeleton and cell signaling. The correlation of the tumor-suppressive function and conformation (open or closed) of neurofibromin 2 has been subject to much speculation, often based on extrapolation from other ERM proteins, and controversy. Here we show that lipid binding results in the open conformation of neurofibromin 2 and that lipid binding is necessary for inhibiting cell proliferation. Collectively, our results provide a mechanism in which the open conformation is unambiguously correlated with lipid binding and localization to the membrane, which are critical for the tumor-suppressive function of neurofibromin 2, thus finally reconciling the long-standing conformation and function debate.

• Authors: Krishna Chinthalapudi, Vinay Mandati, Jie Zheng, Andrew J Sharff, Gerard Bricogne, Patrick R Griffin, Joseph Kissil, Tina Izard
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 1338 (04 06 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29626191 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neurofibromin 2
• Phosphatidylinositol 4,5-Diphosphate

Topics

• Cell Line
• Cell Proliferation
• Crystallography, X-Ray
• HEK293 Cells
• Humans
• Lipid Metabolism
• Neurofibromin 2 (chemistry, genetics, metabolism)
• Phosphatidylinositol 4,5-Diphosphate (metabolism)
• Protein Binding
• Protein Conformation
• Protein Interaction Domains and Motifs
• Signal Transduction