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

doi:10.1038/ncomms2221

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

112 Citations (Scopus)

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 language	English
Article number	1249
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms2221
Publication status	Published - 2012

Bibliographical note

Funding Information:
This work was in part supported by the Chicago Biomedical Consortium with support from the Searl Funds at the Chicago Community Trust (W.C. and H.L.) and the National Institutes of Health GM68849 (W.C.). The work was also supported by the World Class University program R31-2008-000-10105-0 (W.C.) and R33-10128 (K.P.K.) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, and grant A111218-11-PG03 from the National Project for Personalized Genomic Medicine, Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea. We thank Jung H. Kim and Park J. Lee for their preliminary work on NHERF1. We also thank Dr Alejandro Heuck for a generous gift of the PFO expression vector.

All Science Journal Classification (ASJC) codes

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

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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

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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.",

author = "Ren Sheng and Yong Chen and {Yung Gee}, Heon and Ewa Stec and Melowic, {Heather R.} and Blatner, {Nichole R.} and Tun, {Moe P.} and Yonjung Kim and Morten K{\"a}llberg and Fujiwara, {Takahiro K.} and {Hye Hong}, Ji and {Pyo Kim}, Kwang and Hui Lu and Akihiro Kusumi and {Goo Lee}, Min and Wonhwa Cho",

note = "Funding Information: This work was in part supported by the Chicago Biomedical Consortium with support from the Searl Funds at the Chicago Community Trust (W.C. and H.L.) and the National Institutes of Health GM68849 (W.C.). The work was also supported by the World Class University program R31-2008-000-10105-0 (W.C.) and R33-10128 (K.P.K.) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, and grant A111218-11-PG03 from the National Project for Personalized Genomic Medicine, Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea. We thank Jung H. Kim and Park J. Lee for their preliminary work on NHERF1. We also thank Dr Alejandro Heuck for a generous gift of the PFO expression vector.",

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Sheng, R, Chen, Y, Yung Gee, H, Stec, E, Melowic, HR, Blatner, NR, Tun, MP, Kim, Y, Källberg, M, Fujiwara, TK, 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, vol. 3, 1249. https://doi.org/10.1038/ncomms2221

TY - JOUR

T1 - Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins

AU - Sheng, Ren

AU - Chen, Yong

AU - Yung Gee, Heon

AU - Stec, Ewa

AU - Melowic, Heather R.

AU - Blatner, Nichole R.

AU - Tun, Moe P.

AU - Kim, Yonjung

AU - Källberg, Morten

AU - Fujiwara, Takahiro K.

AU - Hye Hong, Ji

AU - Pyo Kim, Kwang

AU - Lu, Hui

AU - Kusumi, Akihiro

AU - Goo Lee, Min

AU - Cho, Wonhwa

N1 - Funding Information: This work was in part supported by the Chicago Biomedical Consortium with support from the Searl Funds at the Chicago Community Trust (W.C. and H.L.) and the National Institutes of Health GM68849 (W.C.). The work was also supported by the World Class University program R31-2008-000-10105-0 (W.C.) and R33-10128 (K.P.K.) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, and grant A111218-11-PG03 from the National Project for Personalized Genomic Medicine, Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea. We thank Jung H. Kim and Park J. Lee for their preliminary work on NHERF1. We also thank Dr Alejandro Heuck for a generous gift of the PFO expression vector.

PY - 2012

Y1 - 2012

N2 - 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.

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ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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