Research article summary (published 30 Jul 2002):

Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms.

Full Abstract

Members of the postsynaptic density-95 (PSD95)/synapse-associated protein-90 (SAP90) family of scaffolding proteins contain a common set of modular protein interaction motifs including PDZ (postsynaptic density-95/Discs large/zona occludens-1), Src homology 3, and guanylate kinase domains, which regulate signaling and plasticity at excitatory synapses. We report that N-terminal alternative splicing of PSD95 generates an isoform, PSD95beta that contains an additional "L27" motif, which is also present in SAP97. Using yeast two hybrid and coimmunoprecipitation assays, we demonstrate that this N-terminal L27 domain of PSD-95beta, binds to an L27 domain in the membrane-associated guanylate kinase calcium/calmodulin-dependent serine kinase, and to Hrs, an endosomal ATPase that regulates vesicular trafficking. By transfecting heterologous cells and hippocampal neurons, we find that interactions with the L27 domain regulate synaptic clustering of PSD95beta. Disrupting Hrs-regulated early endosomal sorting in hippocampal neurons selectively blocks synaptic clustering of PSD95beta but does not interfere with trafficking of the palmitoylated isoform, PSD95alpha. These studies identify molecular and functional heterogeneity in synaptic PSD95 complexes and reveal critical roles for L27 domain interactions and Hrs regulated vesicular trafficking in postsynaptic protein clustering.

Author information

Author/s: Chetkovich, Dane M (DM); Bunn, Robert C (RC); Kuo, Sheng-Han (SH); Kawasaki, Yoshimi (Y); Kohwi, Minoree (M); Bredt, David S (DS);

Affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California 94143-0444, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2002-Aug; vol 22 (issue 15) : pp 6415-25

Dates: Created 2002/08/01; Completed 2002/09/03; Revised 2007/11/15;

PMID: 12151521, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adaptor Proteins, Signal Transducing Alternative Splicing - genetics Amino Acid Motifs - physiology Animals COS Cells Calcium-Calmodulin-Dependent Protein Kinases - metabolism Cells, Cultured Guanylate Kinase Humans Intracellular Signaling Peptides and Proteins Macromolecular Substances Membrane Proteins Molecular Sequence Data

Nerve Tissue Proteins - genetics; metabolism Neurons - cytology; metabolism Nucleoside-Phosphate Kinase - metabolism Phosphoproteins - metabolism Precipitin Tests Protein Isoforms - genetics; metabolism Protein Structure, Tertiary - physiology Protein Transport - physiology Rats Rodentia Sequence Homology, Amino Acid Synapses - metabolism Two-Hybrid System Techniques

Associated Chemicals: Adaptor Proteins, Signal Transducing (0) ; DLG1 protein, human (0) ; DLG4 protein, human (0) ; Dlgh1 protein, rat (0) ; Dlgh4 protein, rat (0) ; Intracellular Signaling Peptides and Proteins (0) ; Macromolecular Substances (0) ; Membrane Proteins (0) ; Nerve Tissue Proteins (0) ; Phosphoproteins (0) ; Protein Isoforms (0) ; hepatocyte growth factor-regulated tyrosine kinase substrate (0) ; postsynaptic density proteins (0) ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17) ; CASK kinases (EC 2.7.4.-) ; Nucleoside-Phosphate Kinase (EC 2.7.4.4) ; Guanylate Kinase (EC 2.7.4.8)

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