Designed folding pathway of modular coiled-coil-based proteins

Jana Aupič, Žiga Strmšek, Fabio Lapenta, David Pahovnik, Tomaž Pisanski, Igor Drobnak, Ajasja Ljubetič and Roman Jerala ()
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Jana Aupič: National Institute of Chemistry
Žiga Strmšek: National Institute of Chemistry
Fabio Lapenta: National Institute of Chemistry
David Pahovnik: National Institute of Chemistry
Tomaž Pisanski: University of Primorska
Igor Drobnak: National Institute of Chemistry
Ajasja Ljubetič: National Institute of Chemistry
Roman Jerala: National Institute of Chemistry

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Natural proteins are characterised by a complex folding pathway defined uniquely for each fold. Designed coiled-coil protein origami (CCPO) cages are distinct from natural compact proteins, since their fold is prescribed by discrete long-range interactions between orthogonal pairwise-interacting coiled-coil (CC) modules within a single polypeptide chain. Here, we demonstrate that CCPO proteins fold in a stepwise sequential pathway. Molecular dynamics simulations and stopped-flow Förster resonance energy transfer (FRET) measurements reveal that CCPO folding is dominated by the effective intra-chain distance between CC modules in the primary sequence and subsequent folding intermediates, allowing identical CC modules to be employed for multiple cage edges and thus relaxing CCPO cage design requirements. The number of orthogonal modules required for constructing a CCPO tetrahedron can be reduced from six to as little as three different CC modules. The stepwise modular nature of the folding pathway offers insights into the folding of tandem repeat proteins and can be exploited for the design of modular protein structures based on a given set of orthogonal modules.

Date: 2021
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DOI: 10.1038/s41467-021-21185-5

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