title: Designed armadillo repeat proteins as general peptide-binding scaffolds: consensus design and computational optimization of the hydrophobic core.
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.
authors.affiliation: Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Parmeggiani
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pellarin
authors.forename: Anders Peter
authors.initials: AP
authors.lastname: Larsen
authors.forename: Gautham
authors.initials: G
authors.lastname: Varadamsetty
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stumpp
authors.forename: Oliver
authors.initials: O
authors.lastname: Zerbe
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.forename: Andreas
authors.initials: A
authors.lastname: Plückthun
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins / Q000737:chemistry* / Q000378:metabolism; D016384:Consensus Sequence; D030562:Databases, Protein; D004926:Escherichia coli; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011487:Protein Conformation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D012441:Saccharomyces cerevisiae
chemical_list: D051186:Armadillo Domain Proteins; D010455:Peptides