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

TY - JOUR

T1 - Designed armadillo repeat proteins as general peptide-binding scaffolds: consensus design and computational optimization of the hydrophobic core.

AU - Parmeggiani, Fabio

AU - Pellarin, Riccardo

AU - Larsen, Anders Peter

AU - Varadamsetty, Gautham

AU - Stumpp, Michael T

AU - Zerbe, Oliver

AU - Caflisch, Amedeo

AU - Plückthun, Andreas

N1 - Keywords: Amino Acid Sequence; Animals; Armadillo Domain Proteins; Consensus Sequence; Databases, Protein; Escherichia coli; Humans; Hydrophobicity; Mice; Models, Molecular; Molecular Sequence Data; Peptides; Protein Conformation; Protein Engineering; Protein Structure, Tertiary; Repetitive Sequences, Amino Acid; Saccharomyces cerevisiae

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1016/j.jmb.2007.12.014

DO - 10.1016/j.jmb.2007.12.014

M3 - Journal article

C2 - 18222472

SN - 0022-2836

VL - 376

SP - 1282

EP - 1304

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

IS - 5

ER -