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Papers In Press, published online ahead of print November 26, 2001
Department of Biophysics, Kyoto University, Kyoto 606-8502
Corresponding Author: doi{at}em.biophys.kyoto-u.ac.jp
The molecular mechanisms underlying the protein assembly at synaptic junctions are thought to be important for neural functions. PSD-95, one of the major postsynaptic density proteins, is composed of three PDZ domains (PDZ1, PDZ2, and PDZ3), an SH3 domain, and a GK domain. It binds to the NMDA glutamate receptor NR2 subunit or to the Shaker type K+ channel Kv1.4, via the PDZ1 or PDZ2 domain, while PDZ3 binds to distinct partners. The intramolecular interaction of these multiple domains has been implicated in efficient protein clustering. We introduced missense and deletion mutations into PDZ1 (PDZ1mDelta) and/or PDZ2 (PDZ2mDelta) of the full-length PSD-95 to disrupt the association of each domain with the target proteins, while preserving the overall structure. The ion channel clustering activities of the PSD-95 mutants were analyzed in COS-1 cells coexpressing each mutant and Kv1.4. The mutant bearing the disfunctional PDZ2 (PSD-95:1-2mDelta) showed significantly reduced clustering efficiency, while the mutant with the disfunctional PDZ1 (PSD-95:1mDelta-2) exhibited activity comparable to the wild-type activity. Furthermore, we also examined the requirements for the position of PDZ2 in full-length PSD-95, by constructing a series of PDZ1-PDZ2 inversion mutants. Surprisingly, the clustering activity of PSD-95:2-1mDelta was severely defective. Taken together, PDZ2, which is endowed with the highest affinity for Kv1.4, is required for efficient ligand binding. In addition, the ligand binding at the position of the second PDZ domain in full-length PSD-95 is prerequisite for efficient and typical cluster formation. This study suggests that the correct placement of the multiple domains in the full-length PSD-95 protein is necessary for the optimal protein activity.
J. Biol. Chem, 10.1074/jbc.M106940200
Submitted on July 23, 2001
Revised on October 26, 2001
Accepted on November 21, 2001
Ligand binding of the second PDZ domain regulates custering of PSD-95 with the Kv1.4 potassium channel
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