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Extending the paradigm

December 2016. ATP-binding cassette (ABC) transporters form a superfamily of integral membrane proteins found in all kingdoms of life, which translocate essential substrates across cellular membranes. Many of these proteins are responsible for multidrug resistance and genetic disorders in humans. These diseases can be a result of either a mutation resulting in dysfunctional protein or overexpression under certain conditions. The generally accepted paradigm links the transport process carried out by specialised transmembrane domains with ATP hydrolysis as the power stroke catalysed by highly conserved, intracellular nucleotide binding domains. In the current study Kaur et al. demonstrate by solid-state NMR combined with biochemical data that ATP hydrolysis in MsbA, a typical ABC exporter involved in lipid A translocation, is intrinsically linked with an adenylate kinase mechanism by which some of the consumed ATPs get recycled. Both mechanisms are associated with the same conserved motifs of the nucleotide-binding domains. The same observations were made for two additional ABC exporters from other organisms suggesting that the coupled mechanism is a general feature at least for members of this protein superfamily subclass. Such a coupled and cyclic catalytic activity adds another layer of complexity to the general molecular mechanism of ABC transporters. However, the presented data also indicate that these proteins might be able to adjust their catalytic capabilities to altered cellular situations: Under conditions of ATP excess, ATP hydrolysis alone dominates the catalytic cycle, while in cases of cellular stress associated with ATP depletion events, a coupling with an adenylate kinase mechanism is advantageous in order to maintain the protein’s transport activity, which is essential for cellular survival. More ...

Clemens Glaubitz
Institute for Biophysical Chemistry & BMRZ
Goethe University Frankfurt


Hundeep Kaur, Andrea Lakatos-Karoly, Ramona Vogel, Anne Nöll, Robert Tampé and Clemens Glaubitz (2016). Coupled ATPase-adenylate kinase activity in ABC transporters. Nature Communications, published online 22 December 2016, DOI 10.1038/NCOMMS13864. Link