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.
Bibliographical noteFunding 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
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)