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

Ren Sheng, Yong Chen, Heon Yung Gee, Ewa Stec, Heather R. Melowic, Nichole R. Blatner, Moe P. Tun, Yonjung Kim, Morten Källberg, Takahiro K. Fujiwara, Ji Hye Hong, Kwang Pyo Kim, Hui Lu, Akihiro Kusumi, Min Goo Lee, Wonhwa Cho

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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.

Original languageEnglish
Article number1249
JournalNature communications
Volume3
DOIs
Publication statusPublished - 2012 Dec 1

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Sheng, R., Chen, Y., Yung Gee, H., Stec, E., Melowic, H. R., Blatner, N. R., Tun, M. P., Kim, Y., Källberg, M., Fujiwara, T. K., Hye Hong, J., Pyo Kim, K., Lu, H., Kusumi, A., Goo Lee, M., & Cho, W. (2012). Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins. Nature communications, 3, [1249]. https://doi.org/10.1038/ncomms2221