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Distinct Ligand Specificity of the Tiam1 and Tiam2 PDZ Domains

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2011, 50, 8, 1296-1308
    Article

    Distinct Ligand Specificity of the Tiam1 and Tiam2 PDZ Domains
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    ‡ Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine
    § Holden Comprehensive Cancer Center
    University of Iowa, Iowa City, Iowa 52242-1109, United States
    ∥ Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, United States
    *To whom correspondence should be addressed. Telephone: (319) 353-4244. Fax: (319) 335-9570. E-mail: [email protected]
    ⊥These authors contributed equally to this work.
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    Biochemistry

    Cite this: Biochemistry 2011, 50, 8, 1296–1308
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi1013613
    Published December 30, 2010
    Copyright © 2010 American Chemical Society
    Request reuse permissions

    Abstract

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    Guanine nucleotide exchange factor proteins of the Tiam family are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These proteins are modular and contain a variety of interaction domains, including a single post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Previous studies suggest that the specificities of the Tiam1 and Tiam2 PDZ domains are distinct. Here, we sought to conclusively define these specificities and determine their molecular origin. Using a combinatorial peptide library, we identified a consensus binding sequence for each PDZ domain. Analysis of these consensus sequences and binding assays with peptides derived from native proteins indicated that these two PDZ domains have overlapping but distinct specificities. We also identified residues in two regions (S0 and S−2 pockets) of the Tiam1 PDZ domain that are important determinants of ligand specificity. Site-directed mutagenesis of four nonconserved residues in these two regions along with peptide binding analyses confirmed that these residues are crucial for ligand affinity and specificity. Furthermore, double mutant cycle analysis of each region revealed energetic couplings that were dependent on the ligand being investigated. Remarkably, a Tiam1 PDZ domain quadruple mutant had the same specificity as the Tiam2 PDZ domain. Finally, analysis of Tiam family PDZ domain sequences indicated that the PDZ domains segregate into four distinct families based on the residues studied here. Collectively, our data suggest that Tiam family proteins have highly evolved PDZ domain−ligand interfaces with distinct specificities and that they have disparate PDZ domain-dependent biological functions.

    Copyright © 2010 American Chemical Society

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    Supporting Information

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    Putative Tiam1 PDZ and Tiam2 PDZ binding proteins (Tables S1 and S2, respectively) and binding curves for various peptides identified in the combinatorial peptide screen (Figure S1). This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 29 publications.

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    23. Thomas Simonson, Benoît Roux. Concepts and protocols for electrostatic free energies. Molecular Simulation 2016, 42 (13) , 1090-1101. https://doi.org/10.1080/08927022.2015.1121544
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    Biochemistry

    Cite this: Biochemistry 2011, 50, 8, 1296–1308
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi1013613
    Published December 30, 2010
    Copyright © 2010 American Chemical Society
    Request reuse permissions

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