期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 4, 页码 E438-E447出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620009114
关键词
ABC transporter; conformational dynamics; membrane proteins; peptide transport; transporter associated with antigen processing
资金
- German Research Foundation [SFB 807]
- Cluster of Excellence, Dynamics of Macromolecular Complexes [EXC 115]
- NIH [GM111126, GM114245]
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 canmediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-angstrom 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.
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