Computational design of a self-assembling symmetrical β-propeller protein

By A. Voet, H. Noguchi, C. Addy, D. Simoncini, D. Terada, S. Unzai, Sam-Yong Park, Kam Y. J. Zhang, J. Tame. 2014

127 citations recorded by the source corpus.

Significance In this study, we have designed and experimentally validated, to our knowledge, the first perfectly symmetrical β-propeller protein. Our results provide insight not only into protein evolution through duplication events, but also into methods for creating designer proteins that self-assemble according to simple arithmetical rules. Such proteins may have very wide uses in bionanotechnology. Furthermore our design approach is both rapid and applicable to many different protein templates. Our novel propeller protein consists of six identical domains known as “blades.” Using a variety of biophysical techniques, we show it to be highly stable and report several high-resolution crystal structures of different forms of the protein. Domain swapping allows us to generate related oligomeric forms with fixed numbers of blades per complex. The modular structure of many protein families, such as β-propeller proteins, strongly implies that duplication played an important role in their evolution, leading to highly symmetrical intermediate forms. Previous attempts to create perfectly symmetrical propeller proteins have failed, however. We have therefore developed a new and rapid computational approach to design such proteins. As a test case, we have created a sixfold symmetrical β-propeller protein and experimentally validated the structure using X-ray crystallography. Each blade consists of 42 residues. Proteins carrying 2–10 identical blades were also expressed and purified. Two or three tandem blades assemble to recreate the highly stable sixfold symmetrical architecture, consistent with the duplication and fusion theory. The other proteins produce different monodisperse complexes, up to 42 blades (180 kDa) in size, which self-assemble according to simple symmetry rules. Our procedure is suitable for creating nano-building blocks from different protein templates of desired symmetry.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

Protein sequence design with a learned potential (2020, background): “Successful de novo protein designs often lack homology to any known sequences despite the fact that de novo structures can qualitatively resemble known folds [9, 7, 116].”
Achievements and Challenges in Computational Protein Design. (2017, methodology): “In 2014 Zhang, Tame and coworkers applied CPD for the design of a self-assembling sixfold perfectly symmetric β-propeller protein [119].”
De novo protein design, a retrospective (2020, background): “…the rubredoxin fold (Nanda et al., 2005), Triosephosphate isomerase (TIM) barrels (Huang et al., 2016b), β-barrels (Dou et al., 2018), β-propellers (Voet et al., 2014), coiled coils (Harbury et al., 1998; Huang et al., 2014; Thomson et al., 2014), and repeat proteins (Brunette et al., 2015), as…”