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 and Wonhwa Cho ()
Additional contact information
Ren Sheng: University of Illinois at Chicago
Yong Chen: University of Illinois at Chicago
Heon Yung Gee: Korea 21 Project for Medical Sciences, Yonsei University College of Medicine
Ewa Stec: University of Illinois at Chicago
Heather R. Melowic: University of Illinois at Chicago
Nichole R. Blatner: University of Illinois at Chicago
Moe P. Tun: University of Illinois at Chicago
Yonjung Kim: Korea 21 Project for Medical Sciences, Yonsei University College of Medicine
Morten Källberg: University of Illinois at Chicago
Takahiro K. Fujiwara: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Institute for Frontier Medical Sciences, Kyoto University
Ji Hye Hong: WCU Program, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea.
Kwang Pyo Kim: WCU Program, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea.
Hui Lu: University of Illinois at Chicago
Akihiro Kusumi: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Institute for Frontier Medical Sciences, Kyoto University
Min Goo Lee: Korea 21 Project for Medical Sciences, Yonsei University College of Medicine
Wonhwa Cho: University of Illinois at Chicago

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2221

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