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Title: Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering

Abstract

The cell adhesion molecule CD44 regulates diverse cellular functions, including cell-cell and cell-matrix interaction, cell motility, migration, differentiation, and growth. In cells, CD44 co-localizes with the membrane-cytoskeleton adapter protein Ezrin, which links the CD44 assembled receptor signaling complexes to the cytoskeletal actin and organizes the spatial and temporal localization of signaling events. Here we report that the cytoplasmic tail of CD44 (CD44ct) is largely disordered and adopts an autoinhibited conformation, which prevents CD44ct from binding directly to activated Ezrin in solution. Binding to the signaling lipid phosphatidylinositol 4,5-biphosphlate (PIP2) disrupts autoinhibition in CD44ct, and activates CD44ct to associate with Ezrin. Further, using contrast variation small angle neutron scattering, we show that PIP2 mediates the assembly of a specific hetero-tetramer complex of CD44ct with Ezrin. This study reveals a novel autoregulation mechanism in the cytoplasmic tail of CD44 and the role of PIP2 in mediating the assembly of multimeric CD44ct-Ezrin complexes. We hypothesize that polyvalent electrostatic interactions are responsible for the assembly of multimeric PIP2-CD44-Ezrin complexes.

Authors:
 [1];  [1];  [2];  [3];  [3];  [3];  [2];  [1];  [1]
  1. City College of New York, NY (United States)
  2. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1185789
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 10; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Khajeh, Jahan Ali, Ju, Jeong Ho, Gupta, Yogesh K., Stanley, Christopher B., Do, Changwoo, Heller, William T., Aggarwal, Aneel K., Callaway, David J.E., and Bu, Zimei. Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering. United States: N. p., 2015. Web. doi:10.1074/jbc.m114.589523.
Khajeh, Jahan Ali, Ju, Jeong Ho, Gupta, Yogesh K., Stanley, Christopher B., Do, Changwoo, Heller, William T., Aggarwal, Aneel K., Callaway, David J.E., & Bu, Zimei. Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering. United States. doi:10.1074/jbc.m114.589523.
Khajeh, Jahan Ali, Ju, Jeong Ho, Gupta, Yogesh K., Stanley, Christopher B., Do, Changwoo, Heller, William T., Aggarwal, Aneel K., Callaway, David J.E., and Bu, Zimei. Thu . "Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering". United States. doi:10.1074/jbc.m114.589523. https://www.osti.gov/servlets/purl/1185789.
@article{osti_1185789,
title = {Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering},
author = {Khajeh, Jahan Ali and Ju, Jeong Ho and Gupta, Yogesh K. and Stanley, Christopher B. and Do, Changwoo and Heller, William T. and Aggarwal, Aneel K. and Callaway, David J.E. and Bu, Zimei},
abstractNote = {The cell adhesion molecule CD44 regulates diverse cellular functions, including cell-cell and cell-matrix interaction, cell motility, migration, differentiation, and growth. In cells, CD44 co-localizes with the membrane-cytoskeleton adapter protein Ezrin, which links the CD44 assembled receptor signaling complexes to the cytoskeletal actin and organizes the spatial and temporal localization of signaling events. Here we report that the cytoplasmic tail of CD44 (CD44ct) is largely disordered and adopts an autoinhibited conformation, which prevents CD44ct from binding directly to activated Ezrin in solution. Binding to the signaling lipid phosphatidylinositol 4,5-biphosphlate (PIP2) disrupts autoinhibition in CD44ct, and activates CD44ct to associate with Ezrin. Further, using contrast variation small angle neutron scattering, we show that PIP2 mediates the assembly of a specific hetero-tetramer complex of CD44ct with Ezrin. This study reveals a novel autoregulation mechanism in the cytoplasmic tail of CD44 and the role of PIP2 in mediating the assembly of multimeric CD44ct-Ezrin complexes. We hypothesize that polyvalent electrostatic interactions are responsible for the assembly of multimeric PIP2-CD44-Ezrin complexes.},
doi = {10.1074/jbc.m114.589523},
journal = {Journal of Biological Chemistry},
number = 10,
volume = 290,
place = {United States},
year = {2015},
month = {1}
}

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