title: Modulation of P-glycoproteins by auxin transport inhibitors is mediated by interaction with immunophilins.
abstract: The immunophilin-like FKBP42 TWISTED DWARF1 (TWD1) has been shown to control plant development via the positive modulation of ABCB/P-glycoprotein (PGP)-mediated transport of the plant hormone auxin. TWD1 functionally interacts with two closely related proteins, ABCB1/PGP1 and ABCB19/PGP19/MDR1, both of which exhibit the ability to bind to and be inhibited by the synthetic auxin transport inhibitor N-1-naphylphtalamic acid (NPA). They are also inhibited by flavonoid compounds, which are suspected modulators of auxin transport. The mechanisms by which flavonoids and NPA interfere with auxin efflux components are unclear. We report here the specific disruption of PGP1-TWD1 interaction by NPA and flavonoids using bioluminescence resonance energy transfer with flavonoids functioning as a classical established inhibitor of mammalian and plant PGPs. Accordingly, TWD1 was shown to mediate modulation of PGP1 efflux activity by these auxin transport inhibitors. NPA bound to both PGP1 and TWD1 but was excluded from the PGP1-TWD1 complex expressed in yeast, suggesting a transient mode of action in planta. As a consequence, auxin fluxes and gravitropism in twd1 roots are less affected by NPA treatment, whereas TWD1 gain-of-function promotes root bending. Our data support a novel model for the mode of drug-mediated P-glycoprotein regulation mediated via protein-protein interaction with immunophilin-like TWD1.
authors.affiliation: Institute of Plant Biology and Zurich-Basel Plant Science Center, University of Zurich, Zurich, Switzerland.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bailly
authors.forename: Valpuri
authors.initials: V
authors.lastname: Sovero
authors.forename: Vincent
authors.initials: V
authors.lastname: Vincenzetti
authors.forename: Diana
authors.initials: D
authors.lastname: Santelia
authors.forename: Dirk
authors.initials: D
authors.lastname: Bartnik
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Koenig
authors.forename: Stefano
authors.initials: S
authors.lastname: Mancuso
authors.forename: Enrico
authors.initials: E
authors.lastname: Martinoia
authors.forename: Markus
authors.initials: M
authors.lastname: Geisler
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D017360:Arabidopsis / Q000378:metabolism*; D029681:Arabidopsis Proteins / Q000737:chemistry; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry; D006720:Homozygote; D020104:Immunophilins / Q000737:chemistry*; D007210:Indoleacetic Acids / Q000737:chemistry*; D049449:Luminescence; D008954:Models, Biological; D018517:Plant Roots / Q000378:metabolism; D011485:Protein Binding; D022021:Tacrolimus Binding Proteins / Q000737:chemistry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C114215:ATPGP1 protein, Arabidopsis; D029681:Arabidopsis Proteins; D005419:Flavonoids; D007210:Indoleacetic Acids; C471286:TWD1 protein, Arabidopsis; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins