Undecided membrane proteins insert in random topologies. Up, down and sideways: it does not really matter.

It is usually assumed that to ensure proper function, membrane proteins must be inserted in a unique topology. However, a number of dimeric small multidrug transporters can function in the membrane in various topologies. Thus, the dimers can be a random mixture of NiCi (N and C termini facing the cell cytoplasm) and NoCo (N and C termini facing the outside) orientation. In addition, the dimer functions whether the two protomers are parallel (N and C termini of both protomers on the same side of the membrane) or antiparallel (N and C termini of each protomer on opposite sides of the membrane). This unique phenomenon provides strong support for a simple mechanism of transport where the directionality is determined solely by the driving force.