title: Caveolin-Na/K-ATPase interactions: role of transmembrane topology in non-genomic steroid signal transduction.
abstract: Progesterone and its polar metabolite(s) trigger the meiotic divisions in the amphibian oocyte through a non-genomic signaling system at the plasma membrane. Published site-directed mutagenesis studies of ouabain binding and progesterone-ouabain competition studies indicate that progesterone binds to a 23 amino acid extracellular loop of the plasma membrane α-subunit of Na/K-ATPase. Integral membrane proteins such as caveolins are reported to form Na/K-ATPase-peptide complexes essential for signal transduction. We have characterized the progesterone-induced Na/K-ATPase-caveolin (CAV-1)-steroid 5α-reductase interactions initiating the meiotic divisions. Peptide sequence analysis algorithms indicate that CAV-1 contains two plasma membrane spanning helices, separated by as few as 1-2 amino acid residues at the cell surface. The CAV-1 scaffolding domain, reported to interact with CAV-1 binding (CB) motifs in signaling proteins, overlaps transmembrane (TM) helix 1. The α-subunit of Na/K-ATPase (10 TM helices) contains double CB motifs within TM-1 and TM-10. Steroid 5α-reductase (6 TM helices), an initial step in polar steroid formation, contains CB motifs overlapping TM-1 and TM-6. Computer analysis predicts that interaction between antipathic strands may bring CB motifs and scaffolding domains into close proximity, initiating allostearic changes. Progesterone binding to the α-subunit may thus facilitate CB motif:CAV-1 interaction, which in turn induces helix-helix interaction and generates both a signaling cascade and formation of polar steroids.
authors.affiliation: Department of Physiology & Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. gene.morrill@einstein.yu.edu
authors.forename: Gene A
authors.initials: GA
authors.lastname: Morrill
authors.forename: Adele B
authors.initials: AB
authors.lastname: Kostellow
authors.forename: Amir
authors.initials: A
authors.lastname: Askari
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051242:Caveolin 1 / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D008540:Meiosis / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010042:Ouabain / Q000737:chemistry; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011894:Rana pipiens; D012756:Sheep; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000378:metabolism; D013552:Swine
chemical_list: D051242:Caveolin 1; D021122:Protein Subunits; D011374:Progesterone; D010042:Ouabain; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000254:Sodium-Potassium-Exchanging ATPase