Triggering “Flash” Assembly of Proteins

Designing protein assemblies whose interactions can be manipulated to respond to a single environmental cue.

Addition of copper ions (Cu II) to protein monomers that are engineered with metal-coordination sites leads to the spontaneous metal-induced assembly of specifically designed protein cages.
Image courtesy of F. Akif Tezcan
Addition of copper ions (Cu II) to protein monomers that are engineered with metal-coordination sites leads to the spontaneous metal-induced assembly of specifically designed protein cages.

The Science

An innovative strategy has been developed to impose pre-defined connectivity of protein partners in response to a specific trigger, which is required for directed assembly of proteins to form uniform cage superstructures.

The Impact

This research addresses a fundamental challenge for designing protein assemblies, allowing manipulation of interactions en masse in response to a single environmental cue, analogous to the way nature constructs very stable protein superstructures through cooperative self-assembly.  The results may find use in applications such as light-energy harvesting and catalysis.


Some proteins are able to assemble into cage-like structures, such as the ubiquitous iron-storing protein ferritin or virus capsids, that can be exploited in nanotechnology because of the ease with which they can be genetically and chemically manipulated. However, the driving forces leading to the cage structure are generally weak, making it very difficult to design and controllably produce “synthetic” materials that combine the distinctive properties of these highly evolved biological containers, such as error-free and stimulus-responsive assembly, with desired functional efficiency. In this work, a new protein engineering strategy has been developed to overcome this obstacle, resulting in the chemically controllable assembly of a ferritin protein cage. First, the protein structure was modified to incorporate chemical groups that selectively bind copper metal ions at specific positions in the constituent proteins that make up ferritin. Then, the existing “native” network of hydrogen-bonding interactions (i.e., weakly bonding interactions between hydrogen atoms and oxygen and nitrogen atoms) within this ferritin cage was eliminated. Importantly, the native interactions between hydrophobic (i.e., resisting mixing with water) ferritin proteins were retained. Subsequent addition of copper ions initiated protein cage self-assembly by correctly aligning proteins having the complementary pre-positioned metal ion binding sites. Simultaneously, the hydrophobic interactions between proteins acted as a “glue” to cement uniform cage formation. Removal of the copper ions did not disrupt cage architecture. The specific insights gained concerning the delicate balance between the hydrogen bonding, metal-ion binding, and hydrophobic forces that control assembly of this synthetic ferritin, may extend to other cage-like protein structures, thus greatly expanding the range of protein assemblies that can be exploited for energy producing applications. For instance, an added benefit of genetically incorporating metal ion centers is that these materials may prove useful for artificial photosynthesis applications since self-assembling plant protein systems with interfacial metal centers such as Photosystem II are some of the most efficient systems for harvesting light and converting the captured light into other forms of energy.


F. Akif Tezcan
UC San Diego


Department of Energy, Office of Science, Basic Energy Sciences Program; Beckman Foundation, Sloan Foundation, and National Science Foundation (crystallographic analyses); X-ray diffraction work was carried out at the Stanford Synchrotron Lightsource (SSRL) user facility.


D. J.E. Huard, K. M. Kane and F. A. Tezcan, “Re-engineering protein interfaces yields copper-inducible ferritin cage assembly”, Nature Chemical Biology, 9, 169 (2013).  [DOI: 10.1038/nchembio.1163]

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Program: BES , MSE

Performer: University , SC User Facilities , BES User Facilities , SSRL

Additional: Collaborations , Non-DOE Interagency Collaboration