Designed armadillo repeat proteins as general peptide-binding scaffolds: consensus design and computational optimization of the hydrophobic core

Fabio Parmeggiani, Riccardo Pellarin, Anders Peter Larsen, Gautham Varadamsetty, Michael T Stumpp, Oliver Zerbe, Amedeo Caflisch, Andreas Plückthun

Research output: Contribution to journalArticle (Academic Journal)peer-review

93 Citations (Scopus)

Abstract

Armadillo repeat proteins are abundant eukaryotic proteins involved in several cellular processes, including signaling, transport, and cytoskeletal regulation. They are characterized by an armadillo domain, composed of tandem armadillo repeats of approximately 42 amino acids, which mediates interactions with peptides or parts of proteins in extended conformation. The conserved binding mode of the peptide in extended form, observed for different targets, makes armadillo repeat proteins attractive candidates for the generation of modular peptide-binding scaffolds. Taking advantage of the large number of repeat sequences available, a consensus-based approach combined with a force field-based optimization of the hydrophobic core was used to derive soluble, highly expressed, stable, monomeric designed proteins with improved characteristics compared to natural armadillo proteins. These sequences constitute the starting point for the generation of designed armadillo repeat protein libraries for the selection of peptide binders, exploiting their modular structure and their conserved binding mode.

Original languageEnglish
Pages (from-to)1282-304
Number of pages23
JournalJournal of Molecular Biology
Volume376
Issue number5
DOIs
Publication statusPublished - 7 Mar 2008

Keywords

  • Amino Acid Sequence
  • Animals
  • Armadillo Domain Proteins
  • Consensus Sequence
  • Databases, Protein
  • Escherichia coli
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides
  • Protein Conformation
  • Protein Engineering
  • Protein Structure, Tertiary
  • Repetitive Sequences, Amino Acid
  • Saccharomyces cerevisiae

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