PROTEIN STRUCTURE AND FOLDING
Crystal Structure of GRIP1 PDZ6-Peptide Complex Reveals the Structural Basis for Class II PDZ Target Recognition and PDZ Domain-mediated Multimerization*

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PDZ domains bind to short segments within target proteins in a sequence-specific fashion. Glutamate receptor-interacting protein (GRIP)/ABP family proteins contain six to seven PDZ domains and interact via the sixth PDZ domain (class II) with the C termini of various proteins including liprin-α. In addition the PDZ456 domain mediates the formation of homo- and heteromultimers of GRIP proteins. To better understand the structural basis of peptide recognition by a class II PDZ domain and PDZ-mediated multimerization, we determined the crystal structures of the GRIP1 PDZ6 domain alone and in complex with a synthetic C-terminal octapeptide of human liprin-α at resolutions of 1.5 and 1.8 Å, respectively. Remarkably, unlike other class II PDZ domains, Ile-736 at αB5 rather than conserved Leu-732 at αB1 makes a direct hydrophobic contact with the side chain of the Tyr at the −2 position of the ligand. Moreover, the peptide-bound structure of PDZ6 shows a slight reorientation of helix αB, indicating that the second hydrophobic pocket undergoes a conformational adaptation to accommodate the bulkiness of the Tyr side chain, and forms an antiparallel dimer through an interface located at a site distal to the peptide-binding groove. This configuration may enable formation of GRIP multimers and efficient clustering of GRIP-binding proteins.

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Published, JBC Papers in Press, December 18, 2002, DOI 10.1074/jbc.M212263200

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This work was supported by grants from the K-JIST project, the Brain Korea 21 Project and Critical Technology 21 (Neurobiology Research Center).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code and .) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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These authors contributed equally to this work.