Dr. Lucy Forrest, NIH-NINDS

How repetition helps: computational studies of pseudo-symmetrical membrane proteins

Transport of small molecules such as neurotransmitters across cell membranes is carried out by specific transport proteins that, for example, couple solute flux to the movement of ions along their concentration gradients. This has been proposed to occur via alternate exposure of the protein’s substrate binding-site to either side of the membrane, requiring at least two distinct conformations of the protein. X-ray crystallographic data for several secondary transporter proteins from diverse families support this hypothesis and provide key insights into specific transport mechanisms, although often only for one of the two essential states. An intriguing feature of these structures is the presence of internal structural repeats with inverted topologies with respect to the membrane. I will show using computational structural modeling, and comparison to experimental data, that these structural repeats encode two degenerate conformations of the same protein. Those repeats therefore provide the origins of alternating-access mechanism in the large majority of secondary transporters. I will also show how the the repeated elements can be considered as tools for guiding identification of binding sites, and for identifying distant structural relationships between membrane protein folds.