LAUSR

In cells, over one third of proteins self-associate with multiple copies of themselves to form symmetric homomers. These protein complexes entail unique geometric and functional properties, underlining the virtue of symmetry in proteins. Yet, symmetry can also pose a risk. In sickle cell disease, the symmetry of hemoglobin exacerbates the effect of a mutation, resulting in harmful fibril formation. Here we assessed the universality of this Achilles heel by determining how readily mutations can induce homomers to further self-assemble. We predicted that mutations solely increasing surface hydrophobicity could frequently induce de novo intermolecular interactions driving polymerization. We investigated twelve distinct homomers and, remarkably, we observed their polymerization in all cases, with seven forming micrometer-long fibrils in vivo. Biophysical measurements and electron microscopy indicated that mutants self-assembled in their folded states. Though surface mutations are often regarded as benign due to their minimal impact on protein stability, we exposed their dramatic potential to trigger de novo interactions and polymerization when compounded by symmetry. Accordingly, an analysis of all symmetric proteins of known structure revealed strategically placed charged residues at sensitive surfaces patches, suggesting a mechanism for protection against mis-assembly in these regions. The potential of symmetric proteins to polymerize upon mutation is thus a general mechanism by which protein fibrils can form in vivo, is a target of negative selection, and can be exploited in protein design and nanotechnology.