Essential Contribution of the Ligand-binding Beta B/Beta C Loop of Pdz1 and Pdz2 in the Regulation of Postsynaptic Clustering, Scaffolding, and Localization of Postsynaptic Density-95.
From: Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan.
The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publish Date: Jan 2006
- ISSN: 1529-2401
- Volume: 26
- Issue: 3
- Pages: 763-74
- Medium: Internet
- Language: English
- Citation (JAMA): Nonaka Mio, Doi Tomoko, Fujiyoshi Yoshinori, et al. Essential Contribution of the Ligand-binding Beta B/Beta C Loop of Pdz1 and Pdz2 in the Regulation of Postsynaptic Clustering, Scaffolding, and Localization of Postsynaptic Density-95.. J. Neurosci. Jan 2006;26:763-74
Abstract
Postsynaptic density-95 (PSD-95), a PSD-95/Discs large/zona occludens-1 (PDZ) domain-containing scaffold protein, clusters many signaling molecules near NMDA-type glutamate receptors in the postsynaptic densities. Although the synaptic localization of PSD-95 requires palmitoylation of two cysteines at the N terminus and the presence of at least one PDZ domain, how the clustering of PSD-95 is initiated and regulated remains essentially unknown. To address this issue, we examined PSD-95 clustering in primary cultured hippocampal neurons expressing full-length PSD-95 mutant proteins lacking the ligand-binding ability of PDZ1, PDZ2, and/or PDZ3. The formation of either excitatory or inhibitory synapses was unaffected. Combinations of individual mutations, however, significantly reduced the PSD-95 clustering index, in an approximately additive manner. The sensitivity to 2-bromo-palmitate and latrunculin A, reagents known to affect PSD-95 turnover, was also augmented. Furthermore, the synaptic recruitment of a PSD-95 ligand, synaptic GTPase-activating protein (synGAP), was significantly impaired, whereas the clustering of other scaffolding proteins, such as Homer 1c, Shank/Synamon, and PSD-93/Chapsin-110 was spared. Intriguingly, overexpression of the PSD-95 PDZ1/2/3 mutants caused the PSD-95 clusters to localize away from the dendritic shaft, resulting in the formation of elongated spines, in an inverse correlation with the overall PDZ-ligand affinity. Expression of a mutant synGAP lacking the PDZ-binding motif replicated both the clustering and spine morphology phenotypes. In conclusion, the ligand-binding affinity of the PDZ domains of PSD-95, contributed in part via its interaction with the C-terminal end of synGAP, plays a critical role in titrating the synaptic clustering of PSD-95 and controlling its tight association with the PSD scaffold, thereby affecting synapse maturation.
Mesh Headings (Keywords): Animals, Cell Count, Cells, Cultured, Intracellular Signaling Peptides and Proteins, Ligands, Membrane Proteins, Mice, Mice, Inbred ICR, Protein Binding, Protein Structure, Tertiary, Rats, Rats, Wistar, Synapses
Check for Full Text / PubMed Unique Identifier (PMID): 16421296
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.