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

Krishna Chinthalapudi, Vinay Mandati, Jie Zheng, Andrew J. Sharff, Gerard Bricogne, Patrick R. Griffin, Joseph Kissil and Tina Izard ()
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Krishna Chinthalapudi: The Scripps Research Institute
Vinay Mandati: The Scripps Research Institute
Jie Zheng: The Scripps Research Institute
Andrew J. Sharff: Global Phasing Ltd.
Gerard Bricogne: Global Phasing Ltd.
Patrick R. Griffin: The Scripps Research Institute
Joseph Kissil: The Scripps Research Institute
Tina Izard: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03648-4

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