The EMBO Lecture: Coiled-coil protein origami designed nanostructures

Proteins are the most advanced nanostructures, defined by the sequence of amino acids. Nature provides a limited number of protein sequences and folds, which have been optimized during evolution. Modular design of polypeptide-based polyhedra was inspired by the DNA-based nanostructures. The folding problem of proteins was bypassed by designing de novo coiled-coil protein origami (CCPO) folds based on the well-understood specificity of coiled-coil dimers and used them as modules to guide the polypeptide chain between vertices of the selected polyhedral cage. The principle was demonstrated by the construction of a nanoscale protein tetrahedral cage from a single polypeptide chain composed of 12 coiled-coil forming segments¹. In this assembly 6 edges of the polyhedron are defined by orthogonal coiled-coil dimers. Introduction of supercharged CC building modules² and protein origami computational design platform CoCoPOD enabled design of protein origami cages that are able to self-assemble in vivo. Complexity of protein origami structures as extended to more than 700 residue proteins with tetrahedral, four-sided pyramid and triangular prism that fold efficiently, with kinetics and stability comparable to globular proteins³. In vivo folding of protein origami opens prospects for new applications of this new type of designed nanostructures.

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• Ljubetič, A., Lapenta, F., GradiÅ¡ar, H., Drobnak, I., Aupič, J., StrmÅ¡ek, Ž., Lainšček, D., Hafner-Bratkovič, I., Majerle, A., Krivec, N., Benčina, M., Pisanski, T., Ćirković Veličković, T., Round, A., Carazo, J.M., Melero, R. and Jerala, R., (2017) Design of in vivo self-assembling coiled-coil protein origami. Nat Biotech, 35:1094-1101.