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Sci. Signal., 8 September 2009
Vol. 2, Issue 87, p. ra50
[DOI: 10.1126/scisignal.2000416]

RESEARCH ARTICLES

Rapid Evolution of Functional Complexity in a Domain Family

Andreas Ernst1*, Stephen L. Sazinsky2, Shirley Hui3,4, Bridget Currell5, Moyez Dharsee3, Somasekar Seshagiri5, Gary D. Bader3,4, and Sachdev S. Sidhu1*{dagger}

1 Department of Protein Engineering, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2 Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E19-563, Cambridge, MA 02139, USA.
3 Banting and Best Department of Medical Research, University of Toronto, Donnelly CCBR, 160 College Street, Toronto, Ontario, Canada M5S 3E1.
4 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
5 Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

* Present address: Banting and Best Department of Medical Research and Department of Molecular Genetics, University of Toronto, Donnelly CCBR, 160 College Street, Toronto, Ontario, Canada M5S 3E1.

Abstract: 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.

{dagger} To whom correspondence should be addressed. E-mail: sachdev.sidhu{at}utoronto.ca

Citation: A. Ernst, S. L. Sazinsky, S. Hui, B. Currell, M. Dharsee, S. Seshagiri, G. D. Bader, S. S. Sidhu, Rapid Evolution of Functional Complexity in a Domain Family. Sci. Signal. 2, ra50 (2009).

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