Abstract
PDZ protein interaction domains are typically selective for C-terminal ligands, but non-C-terminal, 'internal' ligands have also been identified. The PDZ domain from the cell polarity protein Par-6 binds C-terminal ligands and an internal sequence from the protein Pals1/Stardust. The structure of the Pals1–Par-6 PDZ complex reveals that the PDZ ligand-binding site is deformed to allow for internal binding. Whereas binding of the Rho GTPase Cdc42 to a CRIB domain adjacent to the Par-6 PDZ regulates binding of C-terminal ligands, the conformational change that occurs upon binding of Pals1 renders its binding independent of Cdc42. These results suggest a mechanism by which the requirement for a C terminus can be readily bypassed by PDZ ligands and reveal a complex set of cooperative and competitive interactions in Par-6 that are likely to be important for cell polarity regulation.
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Acknowledgements
We thank A. Berglund, T. Stevens, B. Volkman, and members of the Prehoda Lab for helpful comments and suggestions. We thank the support staff at beamline 8.2.1 at the Advanced Light Source for technical assistance. This work was supported by grants from the American Heart Association, National Institutes of Health (GM068032), and a Damon Runyon Scholar Award to K.E.P.
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Supplementary information
Supplementary Fig. 1
Electron density maps. (PDF 10090 kb)
Supplementary Fig. 2
B-factor plot. (PDF 636 kb)
Supplementary Fig. 3
Heteronuclear NOEs. (PDF 653 kb)
Supplementary Fig. 4
Real space correlation coefficients. (PDF 626 kb)
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Penkert, R., DiVittorio, H. & Prehoda, K. Internal recognition through PDZ domain plasticity in the Par-6–Pals1 complex. Nat Struct Mol Biol 11, 1122–1127 (2004). https://doi.org/10.1038/nsmb839
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DOI: https://doi.org/10.1038/nsmb839
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