Membrane protein assembly patterns reflect selection for non‐proliferative structures

Membrane proteins that regulate solute movement are often built from multiple copies of an identical polypeptide chain. These complexes represent striking examples of self‐assembling systems that recruit monomers only until a prescribed level for function is reached. Here we report that three modes of assembly – distinguished by sequence and stoichiometry – describe all helical membrane protein complexes currently solved to high resolution. Using the 13 presently available non‐redundant homo‐oligomeric structures, we show that two of these types segregate with protein function: one produces energy‐dependent transporters, while the other builds channels for passive diffusion. Given such limited routes to functional complexes, membrane proteins that self‐assemble exist on the edge of aggregation, susceptible to mutations that may underlie human diseases.