NeissLock provides an inducible protein anhydride for covalent targeting of endogenous proteins

Arne H. A. Scheu, Sheryl Y. T. Lim, Felix J. Metzner, Shabaz Mohammed and Mark Howarth ()
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Arne H. A. Scheu: University of Oxford
Sheryl Y. T. Lim: University of Oxford
Felix J. Metzner: University of Oxford
Shabaz Mohammed: University of Oxford
Mark Howarth: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract The Neisseria meningitidis protein FrpC contains a self-processing module (SPM) undergoing autoproteolysis via an aspartic anhydride. Herein, we establish NeissLock, using a binding protein genetically fused to SPM. Upon calcium triggering of SPM, the anhydride at the C-terminus of the binding protein allows nucleophilic attack by its target protein, ligating the complex. We establish a computational tool to search the Protein Data Bank, assessing proximity of amines to C-termini. We optimize NeissLock using the Ornithine Decarboxylase/Antizyme complex. Various sites on the target (α-amine or ε-amines) react with the anhydride, but reaction is blocked if the partner does not dock. Ligation is efficient at pH 7.0, with half-time less than 2 min. We arm Transforming Growth Factor-α with SPM, enabling specific covalent coupling to Epidermal Growth Factor Receptor at the cell-surface. NeissLock harnesses distinctive protein chemistry for high-yield covalent targeting of endogenous proteins, advancing the possibilities for molecular engineering.

Date: 2021
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DOI: 10.1038/s41467-021-20963-5

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