Rapid evolution of functional complexity in a domain family.
Multicellular organisms rely on complex, fine-tuned protein networks to respond to environmental changes. We used in vitro evolution to explore the role of domain mutation and expansion in the evolution of network complexity. Using random mutagenesis to facilitate family expansion, we asked how versatile and robust the binding site must be to produce the rich functional diversity of the natural PDZ domain family. From a combinatorial protein library, we analyzed several hundred structured domain variants and found that one-quarter were functional for carboxyl-terminal ligand recognition and that our variant repertoire was as specific and diverse as the natural family. Our results show that ligand binding is hardwired in the PDZ fold and suggest that this flexibility may facilitate the rapid evolution of complex protein interaction networks.
Ernst
Andreas
A
Department of Protein Engineering, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Sazinsky
Stephen L
SL
Hui
Shirley
S
Currell
Bridget
B
Dharsee
Moyez
M
Seshagiri
Somasekar
S
Bader
Gary D
GD
Sidhu
Sachdev S
SS
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019020:Directed Molecular Evolution; D006801:Humans; D008024:Ligands; D016296:Mutagenesis; D017434:Protein Structure, Tertiary
D048868:Adaptor Proteins, Signal Transducing; C413364:ERBIN protein, human; D008024:Ligands