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A metal-trap tests and refines blueprints to engineer cellular protein metalation with different elements

Author

Listed:
  • Sophie E. Clough

    (University of Durham
    University of Durham)

  • Tessa R. Young

    (University of Durham
    University of Durham)

  • Emma Tarrant

    (University of Durham
    University of Durham)

  • Andrew J. P. Scott

    (University of Durham
    University of Durham)

  • Peter T. Chivers

    (University of Durham
    University of Durham)

  • Arthur Glasfeld

    (University of Durham
    University of Durham)

  • Nigel J. Robinson

    (University of Durham
    University of Durham)

Abstract

It has been challenging to test how proteins acquire specific metals in cells. The speciation of metalation is thought to depend on the preferences of proteins for different metals competing at intracellular metal-availabilities. This implies mis-metalation may occur if proteins become mis-matched to metal-availabilities in heterologous cells. Here we use a cyanobacterial MnII-cupin (MncA) as a metal trap, to test predictions of metalation. By re-folding MncA in buffered competing metals, metal-preferences are determined. Relating metal-preferences to metal-availabilities estimated using cellular metal sensors, predicts mis-metalation of MncA with FeII in E. coli. After expression in E. coli, predominantly FeII-bound MncA is isolated experimentally. It is predicted that in metal-supplemented viable cells metal-MncA speciation should switch. MnII-, CoII-, or NiII-MncA are recovered from the respective metal-supplemented cells. Differences between observed and predicted metal-MncA speciation are used to refine estimated metal availabilities. Values are provided as blueprints to guide engineering biological protein metalation.

Suggested Citation

  • Sophie E. Clough & Tessa R. Young & Emma Tarrant & Andrew J. P. Scott & Peter T. Chivers & Arthur Glasfeld & Nigel J. Robinson, 2025. "A metal-trap tests and refines blueprints to engineer cellular protein metalation with different elements," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56199-w
    DOI: 10.1038/s41467-025-56199-w
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    References listed on IDEAS

    as
    1. Kevin J. Waldron & Julian C. Rutherford & Dianne Ford & Nigel J. Robinson, 2009. "Metalloproteins and metal sensing," Nature, Nature, vol. 460(7257), pages 823-830, August.
    2. Deenah Osman & Andrew W. Foster & Junjun Chen & Kotryna Svedaite & Jonathan W. Steed & Elena Lurie-Luke & Thomas G. Huggins & Nigel J. Robinson, 2017. "Fine control of metal concentrations is necessary for cells to discern zinc from cobalt," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    3. Tae Su Choi & F. Akif Tezcan, 2022. "Overcoming universal restrictions on metal selectivity by protein design," Nature, Nature, vol. 603(7901), pages 522-527, March.
    4. Steve Tottey & Kevin J. Waldron & Susan J. Firbank & Brian Reale & Conrad Bessant & Katsuko Sato & Timothy R. Cheek & Joe Gray & Mark J. Banfield & Christopher Dennison & Nigel J. Robinson, 2008. "Protein-folding location can regulate manganese-binding versus copper- or zinc-binding," Nature, Nature, vol. 455(7216), pages 1138-1142, October.
    5. Tessa R. Young & Maria Alessandra Martini & Andrew W. Foster & Arthur Glasfeld & Deenah Osman & Richard J. Morton & Evelyne Deery & Martin J. Warren & Nigel J. Robinson, 2021. "Calculating metalation in cells reveals CobW acquires CoII for vitamin B12 biosynthesis while related proteins prefer ZnII," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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