TY - JOUR
T1 - Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP
AU - Nöll, Anne
AU - Thomas, Christoph
AU - Herbring, Valentina
AU - Zollmann, Tina
AU - Barth, Katja
AU - Mehdipour, Ahmad Reza
AU - Tomasiak, Thomas M.
AU - Brüchert, Stefan
AU - Joseph, Benesh
AU - Abele, Rupert
AU - Oliéric, Vincent
AU - Wang, Meitian
AU - Diederichs, Kay
AU - Hummer, Gerhard
AU - Stroud, Robert M.
AU - Pos, Klaas M.
AU - Tampé, Robert
PY - 2017/1/24
Y1 - 2017/1/24
N2 - 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-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.
AB - 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-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.
KW - ABC transporter
KW - Conformational dynamics
KW - Membrane proteins
KW - Peptide transport
KW - Transporter associated with antigen processing
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U2 - 10.1073/pnas.1620009114
DO - 10.1073/pnas.1620009114
M3 - Article
C2 - 28069938
AN - SCOPUS:85010908132
SN - 0027-8424
VL - 114
SP - E438-E447
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -