Symmetry and structure in P-glycoprotein and ABC transporters - What goes around comes around

The ABC superfamily of membrane transporters is one of the largest classes of proteins across all species and one of the most intensely researched. AB C proteins are involved in the trafficking of a diverse variety of biologic al molecules across cell membranes, with some members implicated in medical syndromes such as cystic fibrosis and multidrug resistance to anti-cancer drugs. In the absence of X-ray crystallographic data, structural informatio n has come from spectroscopy, electron microscopy, secondary structure pred iction algorithms and residue substitution, epitope labelling and cysteine cross-linking studies. These have generally supported a model for the topol ogy of the transmembrane domains of ABC transporters in which a single aque ous pore is formed by a toroidal ring of 12 alpha helices, deployed in two arcs of six helices each. Although this so-called 6 + 6 helix model can be arranged in either mirror or rotational symmetry configurations, experiment al data supports the former. In this review, we put forward arguments again st both configurations of this 6 + 6 helix model, based on what is known ge nerally about symmetry relationships in proteins. We relate these arguments to P-glycoprotein, in particular, and discuss alternative models for the s tructure of ABC transporters in the light of the most recent research.