Designed armadillo repeat proteins as general peptide-binding scaffolds: consensus design and computational optimization of the hydrophobic core.
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.
Parmeggiani
Fabio
F
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Pellarin
Riccardo
R
Larsen
Anders Peter
AP
Varadamsetty
Gautham
G
Stumpp
Michael T
MT
Zerbe
Oliver
O
Caflisch
Amedeo
A
Plückthun
Andreas
A
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
D051186:Armadillo Domain Proteins; D010455:Peptides