Delicate transport molecules

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Frankfurt researchers have elucidated the mechanism of an ABC transporter in detail / Cover story in Nature

Almost all living organisms - from bacteria to humans - harbor sluice-like protein complexes in their cell membranes that carry out unwanted or life-threatening molecules. Not always to the advantage of humans, because in bacteria or cancer cells the so-called ABC transporters are also responsible for resistance to antibiotics or chemotherapy. Researchers at Goethe University and colleagues at the Max Planck Institute for Biophysics in Frankfurt have now succeeded in deciphering the transport mechanism in all stages.

Over the past five years, Robert Tampé's group from the Institute of Biochemistry at Goethe University has worked intensively on preparing samples of sensitive membrane protein complexes in such a way that they can be examined using cryo-electron microscopy. Cryo-electron microscopy provides high-resolution images because it freezes molecules so that blurring caused by movement is minimised.

If complex molecules such as ABC transporters are not only to be imaged sharply, but also observed at work, snapshots of different stages are required. The biochemists led by Tampé were able to specifically induce these stages by supplying the transporter with different concentrations of ATP and ADP. Without the energy supplied in this way, the transporter cannot transport molecules against the concentration gradient between the cell interior and its environment.

In the current issue of the journal Nature, Tampé and his biophysical colleagues show eight high-resolution conformations of an ABC export complex consisting of two different protein subunits. For the first time, the researchers were also able to visualise intermediate stages of the transport process. The editors of Nature have chosen this important discovery as the cover story of the current issue.

"The work could lead to a paradigm shift in structural biology, since all motion states of a cellular machine could be elucidated in almost atomic resolution," explains Prof. Robert Tampé. "Due to this unexpected discovery, we are able to answer controversial questions on the transport mechanism of ABC transporters, which are of particular medical importance. In addition, the researchers were able to observe for the first time how the sluices open outwards or inwards. The resolution of 2.8 angstroms (ten millionths of a millimeter) is the highest resolution with which an ABC transporter structure has ever been imaged using cryo-electron microscopy.