Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins

• Published in: Nature communications 2012, Vol.3 (1), p.1249-1249, Article 1249
• Main Authors: Sheng, Ren, Chen, Yong, Yung Gee, Heon, Stec, Ewa, Melowic, Heather R., Blatner, Nichole R., Tun, Moe P., Kim, Yonjung, Källberg, Morten, Fujiwara, Takahiro K., Hye Hong, Ji, Pyo Kim, Kwang, Lu, Hui, Kusumi, Akihiro, Goo Lee, Min, Cho, Wonhwa
• Format: Article
• Language: English
• Subjects: 631/45/287; 631/45/475/2290; 631/80/86; Binding Sites; Chloride Channels - physiology; Cholesterol; Cholesterol - physiology; Fluorescence Polarization; HEK293 Cells - physiology; Humanities and Social Sciences; Humans; Lipids; Matrix Attachment Regions - physiology; Membranes; Microscopy, Confocal; Molecular Imaging; multidisciplinary; PDZ Domains - physiology; Phosphoproteins - physiology; Physical properties; Proteins; Science; Science (multidisciplinary); Signal Transduction - physiology; Sodium-Hydrogen Exchangers - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2221

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. Cholesterol indirectly regulates intracellular signalling by modulating the physical properties of lipid membranes. Sheng et al. now show that many PDZ domains contain a functional cholesterol-binding motif, revealing that cholesterol can also control the localization and function of signalling proteins directly.