Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins
Open accessAbstract
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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Altering membrane cholesterol might affect lipid raft formation and subsequent PI3K signaling, or membrane-bound cholesterol can directly activate certain downstream signaling proteins such as Akt or Dvl2 (Wnt signaling).
“Enrichment in the PI3K-Akt and Wnt signaling pathways was of interest given reports that altering membrane cholesterol might affect lipid raft formation and subsequent PI3K signaling (42–44), or that membrane-bound cholesterol can directly activate certain downstream signaling proteins such as Akt or Dvl2 (Wnt signaling).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [44]
The Introduction says cholesterol contributes to lipid-raft formation, and the Discussion describes cholesterol-rich rafts as proposed signaling platforms. Neither section links those rafts to PI3K signaling. The paper demonstrates cholesterol binding to PDZ-domain scaffold proteins, not direct activation of Akt or Dvl2. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCertain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane.
“Recent reports suggest that certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane (43, 44, 82–84).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [44]
The Results (‘Many PDZ domains bind cholesterol’; ‘NHERF1-cholesterol binding is essential for its activity’; page not provided) show that several PDZ domains bind cholesterol in plasma-membrane-mimetic vesicles and that cholesterol binding is important for NHERF1-mediated regulation of CFTR. The source does not identify Dvl2 as one of those proteins or show that cholesterol directly activates Dvl2. (LLM, conf=0.88)
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- Authors
- 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.
- Affiliations
- University of Illinois Chicago (US)
- Yonsei University (KR)
- Kyoto University (JP)
- Pohang University of Science and Technology (KR)
- Corresponding author
- Cho, Wonhwa
- Venue
- Nature Communications
- Published
- 2012-12-04
- Volume
- 3
- Issue
- 1
- Pages
- 1249-1249
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3526836
- OpenAlex
- W2011031547
- Cited by
- 179
- References
- 51
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 9 · 2023: 16 · 2022: 14 · 2021: 28 · 2020: 14 · 2019: 18 · 2018: 14 · 2017: 6 · 2016: 13 · 2015: 12 · 2014: 7 · 2013: 5
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Chicago Community Trust
- Chicago Biomedical Consortium
- National Research Foundation
- National Research Foundation of Korea (R31-2008-000-10105-0)
- Ministry of Education, Science and Technology (R33-10128, R31-2008-000–10105-0, A111218-11-PG03)
- National Institutes of Health
- Japan Society for the Promotion of Science (24247029)
- National Institute of General Medical Sciences (GM 68849, R01GM068849, R01GM052598)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- cholesterol, PDZ domain, scaffold proteins, NHERF1, EBP50, cholesterol binding sites, signal transduction, cystic fibrosis transmembrane conductance regulator, CFTR, signaling platforms, lipid rafts, protein-protein interaction
- MeSH terms
- Binding Sites, Cholesterol, Fluorescence Polarization, Humans, Phosphoproteins, Signal Transduction, Sodium-Hydrogen Exchangers, Chloride Channels, Microscopy, Confocal, Matrix Attachment Regions, PDZ Domains, Molecular Imaging, HEK293 Cells
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