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Internal recognition through PDZ domain plasticity in the Par-6–Pals1 complex

Nature Structural & Molecular Biology volume 11, pages 1122–1127 (2004)Cite this article

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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Figure 1: Identification of Par-6 PDZ-binding motifs in Pals1 and Stardust.
Figure 2: Comparison of Par-6 PDZ internal and C-terminal binding.
Figure 3: Critical interactions in Pals1 internal PDZ binding.
Figure 4: Analysis of Par-6 PDZ ligand-binding determinants.
Figure 5: Modes of PDZ C-terminal and internal recognition.

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References

  1. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).

    Article  CAS  Google Scholar 

  2. van Ham, M. & Hendriks, W. PDZ domains-glue and guide. Mol. Biol. Rep. 30, 69–82 (2003).

    Article  CAS  Google Scholar 

  3. Harris, B.Z. & Lim, W.A. Mechanism and role of PDZ domains in signaling complex assembly. J. Cell. Sci. 114, 3219–3231 (2001).

    CAS  PubMed  Google Scholar 

  4. Doyle, D.A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996).

    Article  CAS  Google Scholar 

  5. Songyang, Z. et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275, 73–77 (1997).

    Article  CAS  Google Scholar 

  6. Harris, B.Z., Lau, F.W., Fujii, N., Guy, R.K. & Lim, W.A. Role of electrostatic interactions in PDZ domain ligand recognition. Biochemistry 42, 2797–27805 (2003).

    Article  CAS  Google Scholar 

  7. Hillier, B.J., Christopherson, K.S., Prehoda, K.E., Bredt, D.S. & Lim, W.A. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS–syntrophin complex. Science 284, 812–815 (1999).

    Article  CAS  Google Scholar 

  8. Gee, S.H. et al. Cyclic peptides as non-carboxyl-terminal ligands of syntrophin PDZ domains. J Biol. Chem. 273, 21980–21987 (1998).

  9. Christopherson, K.S., Hillier, B.J., Lim, W.A. & Bredt, D.S. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol. Chem. 274, 27467–27473 (1999).

    Article  CAS  Google Scholar 

  10. Hurd, T.W., Gao, L., Roh, M.H., Macara, I.G. & Margolis, B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat. Cell Biol. 5, 137–142 (2003).

    Article  CAS  Google Scholar 

  11. Lemmers, C. et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol. Biol. Cell 15, 1324–1333 (2004).

    Article  CAS  Google Scholar 

  12. Peterson, F.C., Penkert, R.R., Volkman, B.F. & Prehoda, K.E. Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition. Mol. Cell 13, 665–676 (2004).

    Article  CAS  Google Scholar 

  13. McGee, A.W. et al. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol. Cell 8, 1291–1301 (2001).

    Article  CAS  Google Scholar 

  14. Makarova, O., Roh, M.H., Liu, C.J., Laurinec, S. & Margolis, B. Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1). Gene 302, 21–29 (2003).

    Article  CAS  Google Scholar 

  15. Roh, M.H. et al. The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost. J. Cell Biol. 157, 161–172 (2002).

    Article  CAS  Google Scholar 

  16. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  17. Navaza, J. Implementation of molecular replacement in AMoRe. Acta. Crystallogr. D Biol. Crystallogr. 57, 1367–1372 (2001).

    Article  CAS  Google Scholar 

  18. Brunger, A.T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta. Crystallogr. D 54, 905–921 (1998).

    Article  CAS  Google Scholar 

  19. Jones, T.A., Zou, J.-Y. & Cowan, S.W. Improved methods for building models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  20. Winn, M.D., Isupov, M.N. & Murshudov, G.N. Use of TLS parameters to model anisotropic displacements in macromolecular refinement. Acta. Crystallogr. D 57, 122–133 (2001).

    Article  CAS  Google Scholar 

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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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  1. Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, 97403, Oregon, USA

    Rhiannon R Penkert, Heather M DiVittorio & Kenneth E Prehoda

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  1. Rhiannon R Penkert
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  2. Heather M DiVittorio
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  3. Kenneth E Prehoda
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Correspondence to Kenneth E Prehoda.

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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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