title: Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP.
abstract: ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be regarded as a model system for asymmetric ABC exporters in general, and for TAP in particular.
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Nöll
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Herbring
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Zollmann
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.|Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Barth
authors.affiliation: Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Mehdipour
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tomasiak
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brüchert
authors.affiliation: Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Benesh
authors.initials: B
authors.lastname: Joseph
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
authors.affiliation: Swiss Light Source, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Oliéric
authors.affiliation: Swiss Light Source, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Meitian
authors.initials: M
authors.lastname: Wang
authors.affiliation: Molecular Bioinformatics, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Diederichs
authors.affiliation: Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.|Institute of Biophysics, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Gerhard
authors.identifier: 0000-0001-7768-746X
authors.initials: G
authors.lastname: Hummer
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; stroud@msg.ucsf.edu tampe@em.uni-frankfurt.de.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stroud
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Klaas M
authors.initials: KM
authors.lastname: Pos
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany; stroud@msg.ucsf.edu tampe@em.uni-frankfurt.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D018432:Drug Resistance, Multiple; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D016963:Thermus thermophilus / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; C477327:transporter associated with antigen processing (TAP)
keywords: ABC transporter; conformational dynamics; membrane proteins; peptide transport; transporter associated with antigen processing