title: A semisynthetic fusicoccane stabilizes a protein-protein interaction and enhances the expression of K+ channels at the cell surface.
abstract: Small-molecule stabilization of protein-protein interactions is an emerging field in chemical biology. We show how fusicoccanes, originally identified as fungal toxins acting on plants, promote the interaction of 14-3-3 proteins with the human potassium channel TASK-3 and present a semisynthetic fusicoccane derivative (FC-THF) that targets the 14-3-3 recognition motif (mode 3) in TASK-3. In the presence of FC-THF, the binding of 14-3-3 proteins to TASK-3 was increased 19-fold and protein crystallography provided the atomic details of the effects of FC-THF on this interaction. We also tested the functional effects of FC-THF on TASK channels heterologously expressed in Xenopus oocytes. Incubation with 10 μM FC-THF was found to promote the transport of TASK channels to the cell membrane, leading to a significantly higher density of channels at the surface membrane and increased potassium current.
authors.affiliation: Chemical Genomics Centre of the Max-Planck-Society, 44227 Dortmund, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Anders
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Kristin
authors.initials: K
authors.lastname: Koschinsky
authors.forename: Maria
authors.initials: M
authors.lastname: Bartel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schumacher
authors.forename: Philipp
authors.initials: P
authors.lastname: Thiel
authors.forename: Hajime
authors.initials: H
authors.lastname: Nitta
authors.forename: Regina
authors.initials: R
authors.lastname: Preisig-Müller
authors.forename: Günter
authors.initials: G
authors.lastname: Schlichthörl
authors.forename: Vijay
authors.initials: V
authors.lastname: Renigunta
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Jürgen
authors.initials: J
authors.lastname: Daut
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D004224:Diterpenes; C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain; C533054:fusicoccane A