Efficient and Economical Strategy for Functional Metalloprotein Design


The Science

Many proteins exist naturally as symmetrical homo-oligomers or homopolymers. The emergent structural and functional properties of such protein assemblies have inspired extensive efforts in biomolecular design.

As synthesized by ribosomes, proteins are inherently asymmetric. Thus, they must acquire multiple surface patches that selectively associate to generate the different symmetry elements needed to form higher-order architectures, a daunting task for protein design.

A research group at the University of California San Diego has addressed this problem using an inorganic chemical approach, whereby multiple modes of protein-protein interactions and symmetry are simultaneously achieved by selective, “one-pot” coordination of soft and hard metal ions.

The group solved the structures of several synthesized cage variants using data collected on beam line 9-2 at the Stanford Synchrotron Radiation Lightsource. They showed they were able to design interfaces with 2- and 3-fold symmetry axes using cytochrome cb562 variants.

By incorporating hydroxamate binding motifs with native chelating residues, they were also able to generate a protein cage with distinct metal ions at the symmetry interfaces. And by varying the ratios of Zn and Fe, they were able to generate different cage symmetries.

The new cages closely resembled natural polyhedral protein architectures and are unique in that they are tightly packed and devoid of any large apertures. At the same time, they assemble and disassemble in response to diverse stimuli, owing to their heterobimetallic construction on minimal interprotein-bonding footprints. With varying stoichiometries, these protein cages represent some of the most compositionally complex protein assemblies obtained by design.

Related Links


Golub, E., et al. 2020. “Constructing Protein Polyhedra via Orthogonal Chemical Interactions,” Nature 578, 172–76.  [DOI:10.1038/s41586-019-1928-2]