Assembly reflects evolution of protein complexes

The majority of proteins tend to bind to one or several copies of themselves and assemble as 'homo-oligomeric' complexes — or homomers. Based on the known crystallographic structures of 5,000 such complexes, Levy et al. have derived plausible pathways for the emergence of ever more complex such assemblies during evolution. Using electrospray mass spectrometry, they observe that the same pathways are followed on the shorter timescale of protein assembly in vitro. Homophilic protein interactions are fundamental in biochemical processes such as allostery and the predictive method developed here should help targeting drugs to protein–protein interfaces more efficiently. On the basis of the known crystallographic structures of 5000 'homo-oligomeric' complexes, this study derives plausible pathways for the emergence of ever more complex such assemblies during evolution. Using electrospray mass spectrometry, it is observed that the same pathways are followed on the shorter time-scale of protein assembly in vitro. A homomer is formed by self-interacting copies of a protein unit. This is functionally important1,2, as in allostery3,4,5, and structurally crucial because mis-assembly of homomers is implicated in disease6,7. Homomers are widespread, with 50–70% of proteins with a known quaternary state assembling into such structures8,9. Despite their prevalence, their role in the evolution of cellular machinery10,11 and the potential for their use in the design of new molecular machines12,13, little is known about the mechanisms that drive formation of homomers at the level of evolution and assembly in the cell9,14. Here we present an analysis of over 5,000 unique atomic structures and show that the quaternary structure of homomers is conserved in over 70% of protein pairs sharing as little as 30% sequence identity. Where quaternary structure is not conserved among the members of a protein family, a detailed investigation revealed well-defined evolutionary pathways by which proteins transit between different quaternary structure types. Furthermore, we show by perturbing subunit interfaces within complexes and by mass spectrometry analysis15, that the (dis)assembly pathway mimics the evolutionary pathway. These data represent a molecular analogy to Haeckel’s evolutionary paradigm of embryonic development, where an intermediate in the assembly of a complex represents a form that appeared in its own evolutionary history. Our model of self-assembly allows reliable prediction of evolution and assembly of a complex solely from its crystal structure.