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Repeat Proteins

Armadillo repeat proteins are artificially designed proteins developed in the group of Andreas Plückthun. Armadillo repeat proteins (nArmRP), are characterized by an Armadillo domain, composed by several tandem Armadillo repeats each comrpising 42 amino acid residues. These repeats can mediate interactions to a peptide or a part of protein in an extended conformation. Therein, each Armadillo repeat is able to bind a single specific dipeptide.

The specificity is given by the primary sequence of the repeat: changing the sequence will change the dipeptide target. Interestingly, the individual modules can be arranged in arbitrary order, and hence having access to modules with specific binding capabilities will allow constructing peptide binders from scratch (in silico). Accordingly, these modular-peptide binders could represent a cheap and fast alternative to the more expensive and laborious monoclonal antibodies.

In our group, we investigate the protein-peptide interaction by solution NMR. We determine overall structural features of the designed ArmRPs such as the curvature of the protein (and in particular changes to curvature due to peptide binding) by probing the complex with specifically designed chemical tags, we develop new techniques in isotope labelling to overcome assignment challenges, and exploit the structure modularity to assemble new supramolecular structures.

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Key references

  • S. Cucuzza, M. Sitnik, S. Jurt, E. Michel, W. Dai, P. Ernst, T. Müntener, D. Häussinger, A. Plückthun, O. Zerbe: Unexpected dynamics in femtomolar complexes of binding proteins with peptides, Nature Commun., 14 (2023), 7823.

  • E. Michel, A. Plückthun, O. Zerbe: Peptide binding affinity redistributes preassembled repeat protein fragments (2019) Biol. Chem.400, 393-404.

  • E. Michel, A. Plückthun, O. Zerbe: Peptide-Guided Assembly of Repeat Protein Fragments (2018) Angew. Chem. Int. Ed.57, 4576-4579.

  • C. Ewald, M.T. Christen, R. Watson, M. Mihajlovic, T. Zhou, A. Honegger, A. Plückthun, A. Caflisch, O. Zerbe: A Combined NMR and Computational Approach to Investigate Peptide Binding to a Designed Armadillo Repeat Protein (2015) J. Mol. Biol.427,1916-1933.

  • R. Watson, M. Christen, C. Ewald, F. Bumback, C. Reichen, M. Mihajlovic, E. Schmidt, P. Güntert, A. Plückthun, A. Caflisch, O. Zerbe (2014): Spontaneous Self-Assembly of Engineered Armadillo Repeat Protein Fragments into a Folded Structure, Structure22, 985-995.

  • E. Michel, S. Cucuzza, P. Mittl, O. Zerbe, A. Plückthun: Improved repeat protein stability by combined consensus and computational protein design, Biochemistry, 62, 618-629.

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