Nöll Anne, Thomas Christoph, Herbring Valentina, Zollmann Tina, Barth Katja, Mehdipour Ahmad Reza, Tomasiak Thomas M, Brüchert Stefan, Joseph Benesh, Abele Rupert, Oliéric Vincent, Wang Meitian, Diederichs Kay, Hummer Gerhard, Stroud Robert M, Pos Klaas M, Tampé Robert
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.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E438-E447. doi: 10.1073/pnas.1620009114. Epub 2017 Jan 9.
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.
ABC转运蛋白构成了所有生命领域中最大的蛋白质超家族之一，催化多种底物跨膜转运。处于这一关键位置，ABC转运蛋白可介导癌症治疗中的多药耐药性，其功能障碍与多种疾病相关。在此，我们描述了嗜热栖热菌多药耐药蛋白A和B（TmrAB）异二聚体的2.7埃X射线结构，它不仅与抗原转运复合物TAP具有结构同源性，还能够在人TAP缺陷细胞中恢复抗原加工。TmrAB表现出广泛的肽特异性，并且仅使用一个单一的活性ATP结合位点就能将底物浓缩数千倍。在我们的结构中，TmrAB呈现出不对称的向内状态，并且我们表明以拉链状方式排列的C末端螺旋在引导与底物转运相关的构象变化中起关键作用。总之，TmrAB一般可被视为不对称ABC输出蛋白的模型系统，尤其是TAP的模型系统。
