Research ArticleProtein Domains

Rapid Evolution of Functional Complexity in a Domain Family

Science Signaling  08 Sep 2009:
Vol. 2, Issue 87, pp. ra50
DOI: 10.1126/scisignal.2000416

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Expanding the Universe of PDZ Domains

PDZ domains are peptide recognition modules that typically recognize specific C-terminal sequences, and scaffold proteins containing these domains are important for organizing specialized cellular structures, such as epithelial junctions, neuronal postsynaptic densities, and immunological synapses. PDZ domains exhibit limited sequence conservation; thus Ernst et al. developed a set of PDZ domain variants to study how this family can evolve to produce domains with different binding specificities. They show that random mutations in the binding site of the Erbin PDZ domain produce stable PDZ domains that have specificities that are either similar to those in nature or are new specificities not found in naturally occurring PDZ domains. A selective pressure for ligand binding was not required to produce PDZ variants that bound ligands. The presence of specificities not found in nature suggests that nature has not exhausted the specificity potential of the PDZ fold and that these domains may continue to evolve, leading to new networks of protein interactions. Alternatively, protein interaction networks may be experimentally rewired by synthetic PDZ domains.