Kaspar P. Locher, Allen T. Lee and Douglas C. Rees, Caltech
Transport proteins, embedded in lipid membranes, facilitate the import of nutrients into cells or the release of toxic products into the surrounding medium. The largest and arguably the most important family of membrane transport proteins are the ABC transporters. They are ubiquitous in biology and power the translocation of substrates across the membrane, often against a concentration gradient, by hydrolyzing ATP (Higgins, 1992).
Several human ABC transporters are medically relevant. For example, mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) protein cause cystic fibrosis. A separate subclass of ABC transporters are associated with multidrug resistance in tumors, i.e. the ability of certain cancer cells to extrude cytotoxic agents used in chemotherapy. Yet another ABC transporter, the TAP protein, is critical for the proper functioning of the cellular immune response, as it pumps antigenic polypeptides from the cytoplasm into the endoplasmic reticulum, where they are being loaded onto MHC class I molecules for subsequent presentation on the cell surface. In bacteria, ABC transporters are predominantly involved in nutrient uptake, although they also participate in the export of bacterial toxins and harmful substances, contributing to bacterial multidrug resistance.
Despite the immense amount of biochemical studies, and recent advances in the visualization of ABC transporters, answers to critical questions about their translocation mechanisms have remained elusive. The structure of a bacterial ABC transporter facilitating vitamin B12 import into E. coli, the BtuCD protein, was recently solved from data collected at SSRL. It is the first complete ABC transporter to have its high resolution (3.2 Å) structure determined in the physiological assembly, and it has yielded valuable insight into how ABC transporters work (Locher et al. 2002).
All ABC transporters contain two membrane-spanning domains that harbor a translocation pathway for a specific substrate. Attached are two cytoplasmic adenosine triphosphate-binding cassettes (hence ABC). As the ABC cassettes bind and hydrolyze ATP, conformational changes occur that are transmitted to the membrane-spanning domains, where they induce rearrangements that translocate the substrate from one side of the membrane to the other. The initial motion of the ABC cassettes has been dubbed the power stroke, and it is generally assumed that this rearrangement is similar in all ABC transporters, irrespective of the size of the substrate to be transported or the directionality of the translocation (import or export).
The structure of the BtuCD protein provides insight at just how ABC transporters may carry out their tasks. In particular, three critical elements were visualized for the first time in an intact transporter:
Davidson's perspective, Not
just another ABC transporter, Science 296 1038 (10 May
Issue of Science)
|Last Updated:||14 August 2002|
|Content Owner:||Doug Rees|
|Page Editor:||Lisa Dunn|