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J. Biol. Chem., Vol. 281, Issue 31, 22299-22311, August 4, 2006

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Convergent and Divergent Ligand Specificity among PDZ Domains of the LAP and Zonula Occludens (ZO) Families^*

Yingnan Zhang, Sherry Yeh, Brent A. Appleton, Heike A. Held, P. Jaya Kausalya^¶, Dominic C. Y. Phua^¶, Wai Lee Wong, Laurence A. Lasky, Christian Wiesmann, Walter Hunziker^¶, and Sachdev S. Sidhu¹

From the Departments of Protein Engineering and Assay Automation, Genentech, Inc., South San Francisco, California 94080 and the ^¶Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Republic of Singapore

We present a detailed comparative analysis of the PDZ domains of the human LAP proteins Erbin, Densin-180, and Scribble and the MAGUK ZO-1. Phage-displayed peptide libraries and in vitro affinity assays were used to define ligand binding profiles for each domain. The analysis reveals the importance of interactions with all four C-terminal residues of the ligand, which constitute a core recognition motif, and also the role of interactions with more upstream ligand residues that support and modulate the core binding interaction. In particular, the results highlight the importance of site^-1, which interacts with the penultimate residue of ligand C termini. Site^-1 was found to be monospecific in the Erbin PDZ domain (accepts tryptophan only), bispecific in the first PDZ domain of ZO-1 (accepts tryptophan or tyrosine), and promiscuous in the Scribble PDZ domains. Furthermore, it appears that the level of promiscuity within site^-1 greatly influences the range of potential biological partners and functions that can be associated with each protein. These findings show that subtle changes in binding specificity can significantly alter the range of biological partners for PDZ domains, and the insights enhance our understanding of this diverse family of peptide-binding modules.

Received for publication, March 28, 2006 , and in revised form, May 26, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. E-mail: sidhu{at}gene.com.

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