Controlling protein-protein interactions through metal coordination: Assembly of a 16-helix bundle protein

The prediction, design, and control of protein-protein interactions (PPIs) remain great challenges despite recent advances. Here we describe the chemical control of PPIs through the use of metal coordination, which circumvents the requirement of PPIs for an extensive set of weak interactions spread over a large surface. A non-self-associating four-bundle protein, cytochrome cb (562), with appropriately engineered metal-binding motifs self-assembles to a 16-helix quaternary structure upon addition of equimolar Zn. The crystal structure of the assembly, combined with PFG diffusion NMR and sedimentation velocity experiments, indicates that the oligomerization properties of cytochrome cb (562) are governed entirely by metal coordination without significant thermodynamic bias from specific PPIs.