title: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels.
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.
authors.affiliation: Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Roman Ulrich
authors.initials: RU
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Höhne
authors.forename: Malte
authors.initials: M
authors.lastname: Bartram
authors.forename: Andrea
authors.initials: A
authors.lastname: Calixto
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.forename: Christian
authors.initials: C
authors.lastname: Reinhardt
authors.forename: Fabienne
authors.initials: F
authors.lastname: Koos
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: Elena
authors.initials: E
authors.lastname: Shirokova
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krautwurst
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.forename: Matias
authors.initials: M
authors.lastname: Simons
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiele
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Martin
authors.initials: M
authors.lastname: Chalfie
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
mesh_terms: 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
chemical_list: 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