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Tandem PDZ repeats in glutamate receptor–interacting proteins have a novel mode of PDZ domain–mediated target binding

Abstract

The interaction of the glutamate receptor subunits 2 and 3 (GluR2/3) with multi-PDZ domain glutamate receptor–interacting protein (GRIP) is important for the synaptic trafficking and clustering of the receptors. Binding of GluR2/3 to GRIP requires both the fourth and fifth PDZ domains (PDZ4 and PDZ5) to be covalently linked, although only one PDZ domain is directly involved in binding to the receptor tail. To elucidate the molecular basis of this mode of PDZ domain–mediated target recognition, we solved the solution structures of the PDZ45 tandem and the isolated PDZ4 of GRIP. The two PDZ domains form a compact structure with a fixed interdomain orientation. The interdomain packing and the stable folding of both PDZ domains require a short stretch of amino acids N-terminal to PDZ4 and a conserved linker connecting PDZ4 and PDZ5. PDZ4 contains a deformed aB-bB groove that is unlikely to bind to carboxyl peptides. Instead, the domain stabilizes the structure of PDZ5.

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Figure 1: Structure of PDZ45 tandem repeats of GRIP1.
Figure 2: Molecular interface of PDZ45 repeats.
Figure 3: Solution structure of PDZ4.
Figure 4: Function of the N-terminal extension.
Figure 5: PDZ4 contains a closed βB-αB groove incapable of binding to peptide ligands.

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Acknowledgements

We thank L.E. Kay and R. Muhandiram for collecting the TROSY version of HN(CA)CB and HN(COCA)CB experiments, M. Sheng for critical comments and D. Miller-Martini for reading of the manuscript. This work was supported by grants from the Research Grant Council of Hong Kong and the Human Frontier Science Program Organization to M.Z. The NMR spectrometers used in this work were purchased by the Biotechnology Research Institute of Hong Kong University of Science and Technology.

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Correspondence to Mingjie Zhang.

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Feng, W., Shi, Y., Li, M. et al. Tandem PDZ repeats in glutamate receptor–interacting proteins have a novel mode of PDZ domain–mediated target binding. Nat Struct Mol Biol 10, 972–978 (2003). https://doi.org/10.1038/nsb992

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