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J. Biol. Chem., Vol. 283, Issue 31, 21817-21826, August 1, 2008

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Modulation of P-glycoproteins by Auxin Transport Inhibitors Is Mediated by Interaction with Immunophilins^*

Aurélien Bailly, Valpuri Sovero, Vincent Vincenzetti, Diana Santelia¹, Dirk Bartnik, Bernd W. Koenig^¶, Stefano Mancuso^||, Enrico Martinoia, and Markus Geisler²

From the Institute of Plant Biology and Zurich-Basel Plant Science Center, University of Zurich, CH-8008 Zurich, Switzerland, the Institute of Neuroscience and Biophysics, Research Centre Jülich, D-52425 Jülich, Germany, the ^¶Institute of Physical Biology, Heinrich-Heine University Düsseldorf, D-40225 Düsseldorf, Germany, and the ^||Department of Horticulture, University of Firenze, I-50019 Sesto Fiorentino, Italy

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.

Received for publication, November 27, 2007 , and in revised form, May 19, 2008.

^* This work was supported by funds from the Swiss National Fonds (to M. G. and E. M.) and the Novartis Foundation (M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures," references, and Figs. S1-S6.

¹ Present address: Zurich-Basel Plant Science Ctr., ETH Zürich Inst. of Plant Science, CH-8092 Zurich, Switzerland.

² To whom correspondence should be addressed: University of Zurich, Inst. of Plant Biology and Zurich-Basel Plant Science Ctr., CH-8008 Zurich, Switzerland. Tel.: 41-44-634-8277; Fax: 41-44-634-8204; E-mail: markus.geisler{at}botinst.uzh.ch.

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