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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E438-E447. doi: 10.1073/pnas.1620009114. Epub 2017 Jan 9.

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP.

Author information

1
Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
2
Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
3
Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
5
Swiss Light Source, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
6
Molecular Bioinformatics, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
7
Institute of Biophysics, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
8
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; stroud@msg.ucsf.edu tampe@em.uni-frankfurt.de.
9
Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany; stroud@msg.ucsf.edu tampe@em.uni-frankfurt.de.

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.

KEYWORDS:

ABC transporter; conformational dynamics; membrane proteins; peptide transport; transporter associated with antigen processing

PMID:
28069938
PMCID:
PMC5278451
DOI:
10.1073/pnas.1620009114
[Indexed for MEDLINE]
Free PMC Article

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