Symmetrical protein cages have evolved to fulfil diverse roles in nature, including compartmentalization and cargo delivery1, and have inspired synthetic biologists to create novel protein assemblies via the precise manipulation of protein–protein interfaces. Despite the impressive array of protein cages produced in the laboratory, the design of inducible assemblies remains challenging2,3. Here we demonstrate an ultra-stable artificial protein cage, the assembly and disassembly of which can be controlled by metal coordination at the protein–protein interfaces. The addition of a gold (i)-triphenylphosphine compound to a cysteine-substituted, 11-mer protein ring triggers supramolecular self-assembly, which generates monodisperse cage structures with masses greater than 2 MDa. The geometry of these structures is based on the Archimedean snub cube and is, to our knowledge, unprecedented. Cryo-electron microscopy confirms that the assemblies are held together by 120 S–Aui–S staples between the protein oligomers, and exist in two chiral forms. The cage shows extreme chemical and thermal stability, yet it readily disassembles upon exposure to reducing agents. As well as gold, mercury(ii) is also found to enable formation of the protein cage. This work establishes an approach for linking protein components into robust, higher-order structures, and expands the design space available for supramolecular assemblies to include previously unexplored geometries.
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The data that support the findings of this study are available from the corresponding author on reasonable request. The cryo-EM density maps have been deposited in the Electron Microscopy Data Bank under accession codes EMD-6966 (GNP-produced TRAP-cage), EMD-4443 (left-handed TRAP-cage) and EMD-4444 (right-handed TRAP-cage), and the coordinates have been deposited in the Protein Data Bank under accession numbers 6IB3 (left-handed TRAP-cage) and 6IB4 (right-handed TRAP-cage).
Custom codes used to compute the optimal arrangement of TRAP rings and to predict paradoxical cages are available from the authors on reasonable request.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We thank M. Michalak and R. Pałka for initial TRAP protein production, P. Afonine for assistance with PHENIX real space refinement, M. Kobiałka and O. Woźnicka for TEM imaging, A. Telk and D. Dudek-Adamska for electrothermal atomic absorption spectroscopy experiments and evaluation (with financial support no. POIG.02.02.00-12-023/08), and A. Naskalska for additional experiments. This work was performed in part under the International Cooperative Research Program of the Institute for Protein Research, Osaka University CEMCR-17-05. A.D.M. and J.G.H. were funded by RIKEN Initiative Research Funding awarded to J.G.H. A.D.M. was supported by a Kakenhi Grant-In-Aid for Challenging Exploratory Research (JSPS), no. 2556023. J.G.H., A.B., I.S., A.K. and K.M. were funded by the National Science Centre (NCN, Poland) grant no. 2016/20/W/NZ1/00095 (Symfonia-4). Raman spectroscopy experiments were performed using equipment purchased as part of a project co-funded by the Malopolska Regional Operational Program Measure 5.1 Krakow Metropolitan Area as an important hub of the European Research Area for 2007-2013, project no. MRPO.05.01.00-12-013/15. J.L.P.B. acknowledges support from the EPSRC EP/J01835X/1. T.P.W. was supported under grant no. Homing/2016-2/20. A.F., M.S.K. and P.K. were supported by a ERC starting investigator grant (337757). K.I. was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) from the Japan Agency for Medical Research and Development (AMED). Work at JSI was supported by Slovenian research agency grants nos P1-0112, I0-0005, J7-9398 and EU projects no. 227012 “SPIRIT” and no. 824096 “RADIATE”.
Nature thanks Jeroen Cornelissen, Todd Yeates and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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