skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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:
 [1];  [1];  [1];  [2];  [2];  [1];  [1];  [1]
  1. The Scripps Research Inst., Jupiter, FL (United States)
  2. Global Phasing Ltd., Cambridge (United Kingdom)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health
OSTI Identifier:
1434755
Grant/Contract Number:  
NS077952
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell biology; X-ray crystallography

Citation Formats

Chinthalapudi, Krishna, Mandati, Vinay, Zheng, Jie, Sharff, Andrew J., Bricogne, Gerard, Griffin, Patrick R., Kissil, Joseph, and Izard, Tina. Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03648-4.
Chinthalapudi, Krishna, Mandati, Vinay, Zheng, Jie, Sharff, Andrew J., Bricogne, Gerard, Griffin, Patrick R., Kissil, Joseph, & Izard, Tina. Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2. United States. doi:10.1038/s41467-018-03648-4.
Chinthalapudi, Krishna, Mandati, Vinay, Zheng, Jie, Sharff, Andrew J., Bricogne, Gerard, Griffin, Patrick R., Kissil, Joseph, and Izard, Tina. Fri . "Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2". United States. doi:10.1038/s41467-018-03648-4. https://www.osti.gov/servlets/purl/1434755.
@article{osti_1434755,
title = {Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2},
author = {Chinthalapudi, Krishna and Mandati, Vinay and Zheng, Jie and Sharff, Andrew J. and Bricogne, Gerard and Griffin, Patrick R. and Kissil, Joseph and Izard, Tina},
abstractNote = {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.},
doi = {10.1038/s41467-018-03648-4},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

The Nf2 Tumor Suppressor, Merlin, Functions in Rac-Dependent Signaling
journal, July 2001


Fluorescence Resonance Energy Transfer Analysis of Merlin Conformational Changes
journal, November 2009

  • Hennigan, R. F.; Foster, L. A.; Chaiken, M. F.
  • Molecular and Cellular Biology, Vol. 30, Issue 1
  • DOI: 10.1128/MCB.00248-09

MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes
journal, July 2004

  • Davis, I. W.; Murray, L. W.; Richardson, J. S.
  • Nucleic Acids Research, Vol. 32, Issue Web Server
  • DOI: 10.1093/nar/gkh398

Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase
journal, August 2006

  • Jin, Hongchuan; Sperka, Tobias; Herrlich, Peter
  • Nature, Vol. 442, Issue 7102
  • DOI: 10.1038/nature04856

HDX Workbench: Software for the Analysis of H/D Exchange MS Data
journal, June 2012

  • Pascal, Bruce D.; Willis, Scooter; Lauer, Janelle L.
  • Journal of The American Society for Mass Spectrometry, Vol. 23, Issue 9
  • DOI: 10.1007/s13361-012-0419-6

Merlin differentially associates with the microtubule and actin cytoskeleton
journal, February 1998


The p130 Isoform of Angiomotin Is Required for Yap-Mediated Hepatic Epithelial Cell Proliferation and Tumorigenesis
journal, September 2013


Regulation of the Neurofibromatosis Type 2 Tumor Suppressor Protein, Merlin, by Adhesion and Growth Arrest Stimuli
journal, March 1998

  • Shaw, Reuben J.; McClatchey, Andrea I.; Jacks, Tyler
  • Journal of Biological Chemistry, Vol. 273, Issue 13
  • DOI: 10.1074/jbc.273.13.7757

Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology
journal, July 2002

  • Fernandez-Valle, Cristina; Tang, Yong; Ricard, Jerome
  • Nature Genetics, Vol. 31, Issue 4
  • DOI: 10.1038/ng930

Lipid-Directed Vinculin Dimerization
journal, April 2015


Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization
journal, August 2016

  • Chinthalapudi, Krishna; Rangarajan, Erumbi S.; Brown, David T.
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 34
  • DOI: 10.1073/pnas.1600702113

Molecular Conformation of the Full-Length Tumor Suppressor NF2/Merlin—A Small-Angle Neutron Scattering Study
journal, July 2014

  • Ali Khajeh, Jahan; Ju, Jeong Ho; Atchiba, Moussoubaou
  • Journal of Molecular Biology, Vol. 426, Issue 15
  • DOI: 10.1016/j.jmb.2014.05.011

Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane
journal, February 1998


Regulation of localization and function of the transcriptional co-activator YAP by angiomotin
journal, May 2017


Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
journal, June 2015

  • Li, Youjun; Zhou, Hao; Li, Fengzhi
  • Cell Research, Vol. 25, Issue 7
  • DOI: 10.1038/cr.2015.69

Molecular insights into NF2 /Merlin tumor suppressor function
journal, April 2014


Merlin/Neurofibromatosis Type 2 Suppresses Growth by Inhibiting the Activation of Ras and Rac
journal, January 2007


ERM proteins and merlin: integrators at the cell cortex
journal, August 2002

  • Bretscher, Anthony; Edwards, Kevin; Fehon, Richard G.
  • Nature Reviews Molecular Cell Biology, Vol. 3, Issue 8
  • DOI: 10.1038/nrm882

Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization
journal, June 1998

  • LaJeunesse, Dennis R.; McCartney, Brooke M.; Fehon, Richard G.
  • Journal of Cell Biology, Vol. 141, Issue 7
  • DOI: 10.1083/jcb.141.7.1589

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells
journal, November 2009

  • Lallemand, D.; Saint-Amaux, A. L.; Giovannini, M.
  • Journal of Cell Science, Vol. 122, Issue 22
  • DOI: 10.1242/jcs.045914

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus
journal, February 2010


Contact-dependent inhibition of EGFR signaling by Nf2/Merlin
journal, June 2007

  • Curto, Marcello; Cole, Banumathi K.; Lallemand, Dominique
  • Journal of Cell Biology, Vol. 177, Issue 5
  • DOI: 10.1083/jcb.200703010

Determination of amide hydrogen exchange by mass spectrometry: A new tool for protein structure elucidation
journal, April 1993


A NHERF binding site links the  PDGFR to the cytoskeleton and regulates cell spreading and migration
journal, June 2004


Kibra Functions as a Tumor Suppressor Protein that Regulates Hippo Signaling in Conjunction with Merlin and Expanded
journal, February 2010


Mapping Residual Structure in Intrinsically Disordered Proteins at Residue Resolution Using Millisecond Hydrogen/Deuterium Exchange and Residue Averaging
journal, December 2014

  • Keppel, Theodore R.; Weis, David D.
  • Journal of The American Society for Mass Spectrometry, Vol. 26, Issue 4
  • DOI: 10.1007/s13361-014-1033-6

YAP/TAZ at the Roots of Cancer
journal, June 2016


Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane
journal, October 2005

  • Okada, Tomoyo; Lopez-Lago, Miguel; Giancotti, Filippo G.
  • Journal of Cell Biology, Vol. 171, Issue 2
  • DOI: 10.1083/jcb.200503165

Neurofibromatosis type 2 (NF2): A clinical and molecular review
journal, June 2009


Merlin and ERM proteins: unappreciated roles in cancer development?
journal, November 2003

  • McClatchey, Andrea I.
  • Nature Reviews Cancer, Vol. 3, Issue 11
  • DOI: 10.1038/nrc1213

Role of Merlin/NF2 inactivation in tumor biology
journal, April 2015


Activation of the Tumor Suppressor Merlin Modulates Its Interaction with Lipid Rafts
journal, April 2004


Neurofibromatosis type 2
journal, June 2009


Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

FERM Domain Phosphoinositide Binding Targets Merlin to the Membrane and Is Essential for Its Growth-Suppressive Function
journal, March 2011

  • Mani, T.; Hennigan, R. F.; Foster, L. A.
  • Molecular and Cellular Biology, Vol. 31, Issue 10
  • DOI: 10.1128/MCB.00609-10

Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function
journal, January 2004

  • Surace, Ezequiel I.; Haipek, Carrie A.; Gutmann, David H.
  • Oncogene, Vol. 23, Issue 2
  • DOI: 10.1038/sj.onc.1207142

The Tumor Suppressor Merlin Controls Growth in Its Open State, and Phosphorylation Converts It to a Less-Active More-Closed State
journal, April 2012


Applications of the Restriction Free (RF) cloning procedure for molecular manipulations and protein expression
journal, October 2010

  • Unger, Tamar; Jacobovitch, Yossi; Dantes, Ada
  • Journal of Structural Biology, Vol. 172, Issue 1
  • DOI: 10.1016/j.jsb.2010.06.016

Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease-Causing Point Mutations
journal, March 2000

  • Stokowski, Renee P.; Cox, David R.
  • The American Journal of Human Genetics, Vol. 66, Issue 3
  • DOI: 10.1086/302812

Molecular dissection of radixin: distinct and interdependent functions of the amino- and carboxy-terminal domains.
journal, May 1995

  • Henry, M. D.; Gonzalez Agosti, C.; Solomon, F.
  • The Journal of Cell Biology, Vol. 129, Issue 4
  • DOI: 10.1083/jcb.129.4.1007

p21-activated Kinase Links Rac/Cdc42 Signaling to Merlin
journal, November 2001

  • Xiao, Guang-Hui; Beeser, Alexander; Chernoff, Jonathan
  • Journal of Biological Chemistry, Vol. 277, Issue 2
  • DOI: 10.1074/jbc.C100553200

Structural Basis for Neurofibromatosis Type 2: CRYSTAL STRUCTURE OF THE MERLIN FERM DOMAIN
journal, December 2001

  • Shimizu, Toshiyuki; Seto, Azusa; Maita, Nobuo
  • Journal of Biological Chemistry, Vol. 277, Issue 12
  • DOI: 10.1074/jbc.M109979200

Data processing and analysis with the autoPROC toolbox
journal, March 2011

  • Vonrhein, Clemens; Flensburg, Claus; Keller, Peter
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444911007773

Structure of the ERM Protein Moesin Reveals the FERM Domain Fold Masked by an Extended Actin Binding Tail Domain
journal, April 2000


The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment
journal, December 2013

  • Johnson, Randy; Halder, Georg
  • Nature Reviews Drug Discovery, Vol. 13, Issue 1
  • DOI: 10.1038/nrd4161

MOLREP an Automated Program for Molecular Replacement
journal, December 1997


Cyclic AMP-dependent Protein Kinase Phosphorylates Merlin at Serine 518 Independently of p21-activated Kinase and Promotes Merlin-Ezrin Heterodimerization
journal, February 2004

  • Alfthan, Kaija; Heiska, Leena; Grönholm, Mikaela
  • Journal of Biological Chemistry, Vol. 279, Issue 18
  • DOI: 10.1074/jbc.M313916200

Probing Protein Ligand Interactions by Automated Hydrogen/Deuterium Exchange Mass Spectrometry
journal, February 2006

  • Chalmers, Michael J.; Busby, Scott A.; Pascal, Bruce D.
  • Analytical Chemistry, Vol. 78, Issue 4
  • DOI: 10.1021/ac051294f

    Works referencing / citing this record:

    X-Ray Diffraction data from Protein, source of 6CDS structure
    dataset, January 2018