Infinite assembly of folded proteins [IRB Research Nodes Seminar]

About 50% of the proteins of known structure form symmetric complexes. Symmetry confers unique geometric and functional properties but poses a risk. In sickle cell disease, the symmetry of hemoglobin exacerbates the effect of a mutation, triggering its assembly into harmful fibrils. We examined the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations to increase the surface hydrophobicity in 12 symmetric complexes. Remarkably, they all responded by forming supramolecular assemblies in vitro and in vivo upon their expression in S. cerevisiae. We distinguish these assemblies from aggregates because proteins retain a folded structure. Supramolecular assemblies appear to form readily during evolution, prompting us to investigate how cells interact with them. We performed systematic colocalization experiments between yeast chaperones and distinct assemblies. We also evaluated whether specific knock-out backgrounds sensitize cells to the presence of such assemblies. Through these experiments, we explore interaction networks connecting these supramolecular assemblies to the cell protein machinery.