title: Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins.
abstract: Cholesterol is known to modulate the physical properties of cell membranes, but its direct involvement in cellular signaling has not been thoroughly investigated. Here we show that cholesterol specifically binds many PDZ domains found in scaffold proteins, including the N-terminal PDZ domain of NHERF1/EBP50. This modular domain has a cholesterol-binding site topologically distinct from its canonical protein-binding site and serves as a dual-specificity domain that bridges the membrane and juxta-membrane signaling complexes. Disruption of the cholesterol-binding activity of NHERF1 largely abrogates its dynamic co-localization with and activation of cystic fibrosis transmembrane conductance regulator, one of its binding partners in the plasma membrane of mammalian cells. At least seven more PDZ domains from other scaffold proteins also bind cholesterol and have cholesterol-binding sites, suggesting that cholesterol modulates cell signaling through direct interactions with these scaffold proteins. This mechanism may provide an alternative explanation for the formation of signaling platforms in cholesterol-rich membrane domains.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Sheng
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Heon
authors.initials: H
authors.lastname: Yung Gee
authors.forename: Ewa
authors.initials: E
authors.lastname: Stec
authors.forename: Heather R
authors.initials: HR
authors.lastname: Melowic
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Blatner
authors.forename: Moe P
authors.initials: MP
authors.lastname: Tun
authors.forename: Yonjung
authors.initials: Y
authors.lastname: Kim
authors.forename: Morten
authors.initials: M
authors.lastname: Källberg
authors.forename: Takahiro K
authors.initials: TK
authors.lastname: Fujiwara
authors.forename: Ji
authors.initials: J
authors.lastname: Hye Hong
authors.forename: Kwang
authors.initials: K
authors.lastname: Pyo Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kusumi
authors.forename: Min
authors.initials: M
authors.lastname: Goo Lee
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
mesh_terms: D001665:Binding Sites; D018118:Chloride Channels / Q000502:physiology; D002784:Cholesterol / Q000502:physiology*; D005454:Fluorescence Polarization; D057809:HEK293 Cells / Q000502:physiology; D006801:Humans; D045170:Matrix Attachment Regions / Q000502:physiology; D018613:Microscopy, Confocal; D057054:Molecular Imaging; D054731:PDZ Domains / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
chemical_list: D018118:Chloride Channels; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D002784:Cholesterol