Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels
- Tobias B. Huber*,
- Bernhard Schermer*,
- Roman Ulrich Müller*,
- Martin Höhne*,
- Malte Bartram*,
- Andrea Calixto†,
- Henning Hagmann*,
- Christian Reinhardt*,‡,
- Fabienne Koos*,
- Karl Kunzelmann§,
- Elena Shirokova¶,
- Dietmar Krautwurst¶,
- Christian Harteneck‖,
- Matias Simons*,
- Hermann Pavenstädt‡,
- Dontscho Kerjaschki**,
- Christoph Thiele††,
- Gerd Walz*,
- Martin Chalfie†,‡‡, and
- Thomas Benzing*,§§
- *Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany;
- ‡University Hospital Münster, D-48129 Münster, Germany;
- †Department of Biological Sciences, Columbia University, New York, NY 10027-6902;
- §Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;
- ¶Department of Molecular Genetics, German Institute of Human Nutrition, 14558 Nuthetal, Germany;
- ‖Pharmacology, Charité, University of Berlin, 14050 Berlin, Germany;
- **Department of Pathology, University of Vienna, A-1010 Vienna, Austria; and
- ††Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
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Contributed by Martin Chalfie, September 5, 2006
Abstract
The prohibitin (PHB)-domain proteins are membrane proteins that regulate a variety of biological activities, including mechanosensation, osmotic homeostasis, and cell signaling, although the mechanism of this regulation is unknown. We have studied two members of this large protein family, MEC-2, which is needed for touch sensitivity in Caenorhabditis elegans, and Podocin, a protein involved in the function of the filtration barrier in the mammalian kidney, and find that both proteins bind cholesterol. This binding requires the PHB domain (including palmitoylation sites within it) and part of the N-terminally adjacent hydrophobic domain that attaches the proteins to the inner leaflet of the plasma membrane. By binding to MEC-2 and Podocin, cholesterol associates with ion-channel complexes to which these proteins bind: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. Both the MEC-2-dependent activation of mechanosensation and the Podocin-dependent activation of TRPC channels require cholesterol. Thus, MEC-2, Podocin, and probably many other PHB-domain proteins by binding to themselves, cholesterol, and target proteins regulate the formation and function of large protein–cholesterol supercomplexes in the plasma membrane.
Footnotes
- ‡‡To whom correspondence may be addressed at: Department of Biological Sciences, Columbia University, 1012 Fairchild Center, M.C. 2446 New York, NY 10027. E-mail: mc21{at}columbia.edu
- §§To whom correspondence may be addressed at: Renal Division, University Hospital Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany. E-mail: thomas.benzing{at}uniklinik-freiburg.de
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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 20, 2004.
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Author contributions: T.B.H., B.S., and R.U.M. contributed equally to this work. T.B.H., B.S., R.U.M., M.H., M.B., A.C., H.H., C.R., F.K., K.K., E.S., D. Krautwurst, C.H., M.S., D. Kerjaschki, G.W., M.C., and T.B. designed research; T.B.H., B.S., R.U.M., M.H., M.B., A.C., H.H., C.R., F.K., K.K., E.S., D. Krautwurst, C.H., M.S., D. Kerjaschki, M.C., and T.B. performed research; C.H., H.P., and C.T. contributed new reagents/analytic tools; T.B.H., B.S., R.U.M., M.H., M.B., K.K., D. Krautwurst, H.P., D. Kerjaschki, C.T., G.W., M.C., and T.B. analyzed data; and D. Krautwurst, M.C., and T.B. wrote the paper.
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Conflict of interest statement: Columbia University has filed a provisional patent application based on this research.
- Abbreviations:
- MBCD,
- methyl-β-cyclodextrine;
- NMDG,
- n-methyl-d-glucamine;
- OAG,
- oleoyl-2-acetyl-sn-glycerol;
- PHB,
- prohibitin.
- © 2006 by The National Academy of Sciences of the USA
