Abstract
Helical membrane proteins such as transporters, receptors, or channels often exhibit structural symmetry. Symmetry is perfect in homo-oligomers consisting of two or more copies of the same protein chain. Intriguingly, in single chain membrane proteins, often internal pseudo-symmetry is observed, in particular in transporters and channels. In several cases single chain proteins with pseudo-symmetry exist, that share the fold with homo-oligomers suggesting evolutionary pathways that involve gene duplication and fusion. It has been hypothesized that such evolutionary pathways allow for the rapid development of large proteins with novel functionality. At the same time symmetry can be leveraged to recognize highly symmetric substrates such as ions. Here we review helical transporter proteins with an inverted two-fold pseudo-symmetry. In this special scenario the symmetry axis lies in the membrane plane. As a result, the putative ancestral monomeric protein would insert in both directions into the membrane and its open-to-the-inside and open-to-the-outside conformations would be structurally identical and iso-energetic, giving a possible evolutionary pathway to create a transporter protein that needs to flip between the two states.
Highlights
Helical membrane proteins such as transporters, receptors, or channels often exhibit structural symmetry
In several cases single chain proteins with pseudo-symmetry exist, that share the fold with homo-oligomers suggesting evolutionary pathways that involve gene duplication and fusion
It has been hypothesized that such evolutionary pathways allow for the rapid development of large proteins with novel functionality
Summary
In the realm of soluble proteins, ten folds are over-represented proteins with complex functions rapidly in nature. Likely exist because nature evolved existent protein folds as opposed to generating new folds [2] Six of these ten superfolds display pseudosymmetry, i.e. can be seen as a repeat of usually two or more copies of nearly identical structural subunits. It has been postulated that symmetry at the fold level evolved via gene duplication and fusion events from homo-oligomeric proteins [4,5] (Figure 1). Mutations cause a switched in protein’s B bias to aCenter for Structural Biology, Department of Chemistry, Vanderbilt insert into the membrane resulting in proteins of opposite topology. For path b, this means mutations have stabilized each protein in its respective.
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