Large protein complex interfaces have evolved to promote cotranslational assembly

Assembly pathways of protein complexes should be precise and efficient to minimise misfolding and unwanted interactions with other proteins in the cell. One way to achieve this efficiency is by seeding assembly pathways during translation via the cotranslational assembly of subunits. While recent evidence suggests that such cotranslational assembly is widespread, little is known about the properties of protein complexes associated with the phenomenon. Here, using a combination of proteome-specific protein complex structures and publicly available ribosome profiling data, we show that cotranslational assembly is particularly common between subunits that form large intermolecular interfaces. To test whether large interfaces have evolved to promote cotranslational assembly, as opposed to cotranslational assembly being a non-adaptive consequence of large interfaces, we compared the sizes of first and last translated interfaces of heteromers in bacterial, yeast, and human complexes. We detect a clear preference in N-terminal interfaces, which will be translated first and thus more likely to form cotranslationally, to be larger than C-terminal interfaces, suggesting that large interfaces have evolved as a means to maximise the chance of successful cotranslational subunit binding.