Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels.
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.
Huber
Tobias B
TB
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Schermer
Bernhard
B
Müller
Roman Ulrich
RU
Höhne
Martin
M
Bartram
Malte
M
Calixto
Andrea
A
Hagmann
Henning
H
Reinhardt
Christian
C
Koos
Fabienne
F
Kunzelmann
Karl
K
Shirokova
Elena
E
Krautwurst
Dietmar
D
Harteneck
Christian
C
Simons
Matias
M
Pavenstädt
Hermann
H
Kerjaschki
Dontscho
D
Thiele
Christoph
C
Walz
Gerd
G
Chalfie
Martin
M
Benzing
Thomas
T
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D000091402:Prohibitins; D011485:Protein Binding; D012680:Sensitivity and Specificity; D016415:Sequence Alignment
D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; C096705:MEC-2 protein, C elegans; D008565:Membrane Proteins; C407223:NPHS2 protein; C000717328:PHB protein, human; D000091402:Prohibitins; C000717338:prohibitin 2, C elegans; D002784:Cholesterol