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 that links the CD44 assembled receptor signaling complexes to the cytoskeletal actin network, which organizes the spatial and temporal localization of signaling events. Here we report that the cytoplasmic tail of CD44 (CD44ct) is largely disordered. Upon binding to the signaling lipid phosphatidylinositol 4,5-bisphosphate (PIP2), CD44ct clusters into aggregates. Further, contrary to the generally accepted model, CD44ct does not bind directly to the FERM domain of Ezrin or to the full-length Ezrin but only forms a complex with FERM or with the full-length Ezrin in the presence of PIP2. Using contrast variation small angle neutron scattering, we show that PIP2 mediates the assembly of a specific heterotetramer complex of CD44ct with Ezrin. This study reveals the role of PIP2 in clustering CD44 and in assembling multimeric CD44-Ezrin complexes. We hypothesize that polyvalent electrostatic interactions are responsible for the assembly of CD44 clusters and the multimeric PIP2-CD44-Ezrin complexes.
authors.affiliation: From the Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031, the School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031.
authors.forename: Jahan Ali
authors.initials: JA
authors.lastname: Khajeh
authors.affiliation: From the Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031.
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Ju
authors.affiliation: the Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Yogesh K
authors.initials: YK
authors.lastname: Gupta
authors.affiliation: the Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Stanley
authors.affiliation: the Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831.
authors.forename: Changwoo
authors.initials: C
authors.lastname: Do
authors.affiliation: the Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831.
authors.forename: William T
authors.initials: WT
authors.lastname: Heller
authors.affiliation: the Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
authors.affiliation: From the Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031.
authors.forename: David J E
authors.initials: DJ
authors.lastname: Callaway
authors.affiliation: From the Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031, zbu@ccny.cuny.edu.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Bu
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000302:isolation & purification; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D015398:Signal Transduction / Q000235:genetics; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D046912:Multiprotein Complexes; D019269:Phosphatidylinositol 4,5-Diphosphate; D000099149:Ezrin
keywords: CD44; Cell Adhesion; Cell Adhesion Molecule; Ezrin; Neutron Scattering; Phosphatidylinositol