I came across this interesting article(pdf here) on how proteins have an easy time forming large multi-protein complexes, so much so that there’s often purifying selection against this tendency:
The self-association of proteins into symmetric complexes is ubiquitous in all kingdoms of life. Symmetric complexes possess unique geometric and functional properties, but their internal symmetry can pose a risk. In sickle-cell disease, the symmetry of haemoglobin exacerbates the effect of a mutation, triggering assembly into harmful fibrils. Here we examine the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations solely designed to increase surface hydrophobicity among 12 distinct symmetric complexes from Escherichia coli. Notably, all responded by forming supramolecular assemblies in vitro, as well as in vivo upon heterologous expression in Saccharomyces cerevisiae. Remarkably, in four cases, micrometre-long fibrils formed in vivo in response to a single point mutation. Biophysical measurements and electron microscopy revealed that mutants self-assembled in their folded states and so were not amyloid-like. Structural examination of 73 mutants identified supramolecular assembly hot spots predictable by geometry. A subsequent structural analysis of 7,471 symmetric complexes showed that geometric hot spots were buffered chemically by hydrophilic residues, suggesting a mechanism preventing mis-assembly of these regions. Thus, point mutations can frequently trigger folded proteins to self-assemble into higher-order structures. This potential is counterbalanced by negative selection and can be exploited to design nanomaterials in living cells.
Some key take-home messages with implications for the evolution of those large, visually stunning protein complexes some argue give “an appearance of design” and are supposedly too unlikely to evolve.
We investigated the capacity of surface mutations to trigger new interactions leading to supramolecular assembly. We employed a strategy consisting of an increase in surface hydrophobicity with no regard for other factors such as geometrical or charge complementarity. In contrast to classic protein engineering experiments in which de novo properties are selected from libraries containing 106 to 109 mutants, we created only a few mutants (<10) per protein studied. The simplicity of our strategy makes our results uniquely amenable to evolutionary interpretation, as any phenotype we observe should often be sampled during evolution.
This work demonstrates that protein surfaces are prone to interact by chance and that amplification of such interactions by symmetry can drive supramolecular assembly. This under-appreciated property, in fact, is the basis for protein X-ray crystallography, which requires proteins to self-interact and assemble into crystals. In that respect, it is notable that aggregation-inducing mutations are dogmatically interpreted in the context of misfolding. Our work indicates that a ready pathway to aggregation is the uncontrolled assembly of folded proteins (Fig. 4d). This pathway, which may be further amplified by co-localization26, will be important to consider in future studies predicting the molecular consequences of mutations, including single nucleotide polymorphisms.
Our observations imply that supramolecular assemblies of folded proteins are frequently sampled by evolution. Consistent with this view, recent works have revealed that specific proteins can self-assemble reversibly into foci27,28 or fibers29 in response to changes in cell physiology30 (Supplementary Text 1). The ease with which they can evolve, evidenced here, suggests that many more exist.
There are also some pretty cool figures, including cry-electron microscopic images of some of the rather huge molecular complexes that were triggered by these simple point-mutations in the respective proteins.