Modular peptide binding: From a comparison of natural binders to designed armadillo repeat proteins |
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Affiliation: | 1. Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany;2. Institute of Biochemistry, University of Erlangen-Nuremberg, Fahrstr. 17, 91054 Erlangen, Germany;1. Biochemisches Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland;2. Biozentrum, Universität Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland |
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Abstract: | Several binding scaffolds that are not based on immunoglobulins have been designed as alternatives to traditional monoclonal antibodies. Many of them have been developed to bind to folded proteins, yet cellular networks for signaling and protein trafficking often depend on binding to unfolded regions of proteins. This type of binding can thus be well described as a peptide–protein interaction. In this review, we compare different peptide-binding scaffolds, highlighting that armadillo repeat proteins (ArmRP) offer an attractive modular system, as they bind a stretch of extended peptide in a repeat-wise manner. Instead of generating each new binding molecule by an independent selection, preselected repeats – each complementary to a piece of the target peptide – could be designed and assembled on demand into a new protein, which then binds the prescribed complete peptide. Stacked armadillo repeats (ArmR), each typically consisting of 42 amino acids arranged in three α-helices, build an elongated superhelical structure which enables binding of peptides in extended conformation. A consensus-based design approach, complemented with molecular dynamics simulations and rational engineering, resulted in well-expressed monomeric proteins with high stability. Peptide binders were selected and several structures were determined, forming the basis for the future development of modular peptide-binding scaffolds. |
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Keywords: | Protein engineering Libraries Proteomics Protein design Repeat proteins Peptide binding Protein–peptide interactions |
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