Computational design of symmetrical eight-bladed β-propeller proteins

IUCrJ. 2019 Jan 1;6(Pt 1):46-55. doi: 10.1107/S205225251801480X.

Abstract

β-Propeller proteins form one of the largest families of protein structures, with a pseudo-symmetrical fold made up of subdomains called blades. They are not only abundant but are also involved in a wide variety of cellular processes, often by acting as a platform for the assembly of protein complexes. WD40 proteins are a subfamily of propeller proteins with no intrinsic enzymatic activity, but their stable, modular architecture and versatile surface have allowed evolution to adapt them to many vital roles. By computationally reverse-engineering the duplication, fusion and diversification events in the evolutionary history of a WD40 protein, a perfectly symmetrical homologue called Tako8 was made. If two or four blades of Tako8 are expressed as single polypeptides, they do not self-assemble to complete the eight-bladed architecture, which may be owing to the closely spaced negative charges inside the ring. A different computational approach was employed to redesign Tako8 to create Ika8, a fourfold-symmetrical protein in which neighbouring blades carry compensating charges. Ika2 and Ika4, carrying two or four blades per subunit, respectively, were found to assemble spontaneously into a complete eight-bladed ring in solution. These artificial eight-bladed rings may find applications in bionanotechnology and as models to study the folding and evolution of WD40 proteins.

Keywords: WD40 proteins; bioinformatics; computational modelling; molecular simulation; protein structure; structural biology; β-propeller proteins.

Grant support

This work was funded by Fonds Wetenschappelijk Onderzoek grants G0F9316N, G0E4717N, G051917N, and ASP17. Japan Society for the Promotion of Science grant Kakenhi-B to Jeremy R. H. Tame. Agence Nationale de la Recherche grant ANR-16-C40-0028 to Thomas Schiex.