Self-assembly of switchable protein nanocages via allosteric effect

Abstract

Protein cages have promising applications in highly efficient gene transportation. Many methods of engineering protein–interface interactions have been developed to build such viral mimics. Missing in current approaches is how to turn off the interactions and unpack the protein shell for controlled cargo delivery. Here, we present a concise protein allosteric strategy to create protein nanocages with dismountable coats. This strategy highlights that the precise self-assembly of coat protein only relies on allosterically driven protein–ligand interactions rather than conventional oligomeric protein fusion. Utilizing common calmodulin (CaM) as an allosteric protein element, its Ca2+-mediated conformational interconversion between folded and unfolded states can activate and deactivate its recognition of a specific ligand, thus triggering switchable assembling and uncoating of the protein–ligand supramolecular cages. Moreover, the size, geometry, and architecture of these protein cages can be tailored by modulating the ligand chemistry. Since this new strategy for bottom-up construction of protein cages requires neither protein engineering nor protein interfacial design, we envision that it has potential applications in other allosteric protein families and will offer new vistas on building dynamic and smart virus mimics.