Journal
NATURE CHEMICAL BIOLOGY
Volume 9, Issue 6, Pages 362-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1248
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Funding
- Slovenian Research Agency [J2-2131, P4-0176]
- Excellent NMR-Future Innovation for Sustainable Technologies Centre of Excellence
- European Union regional development funds
- US National Institutes of Health [R01 GM083960, R01 GM54762]
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Protein structures evolved through a complex interplay of cooperative interactions, and it is still very challenging to design new protein folds de novo. Here we present a strategy to design self-assembling polypeptide nanostructured polyhedra based on modularization using orthogonal dimerizing segments. We designed and experimentally demonstrated the formation of the tetrahedron that self-assembles from a single polypeptide chain comprising 12 concatenated coiled coil-forming segments separated by flexible peptide hinges. The path of the polypeptide chain is guided by a defined order of segments that traverse each of the six edges of the tetrahedron exactly twice, forming coiled-coil dimers with their corresponding partners. The coincidence of the polypeptide termini in the same vertex is demonstrated by reconstituting a split fluorescent protein in the polypeptide with the correct tetrahedral topology. Polypeptides with a deleted or scrambled segment order fail to self-assemble correctly. This design platform provides a foundation for constructing new topological polypeptide folds based on the set of orthogonal interacting polypeptide segments.
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