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The Journal of Neuroscience, August 1, 2002, 22(15):6415-6425
Postsynaptic Targeting of Alternative Postsynaptic Density-95
Isoforms by Distinct Mechanisms
Dane M.
Chetkovich1, 2, *,
Robert C.
Bunn1, *,
Sheng-Han
Kuo1,
Yoshimi
Kawasaki1,
Minoree
Kohwi1, and
David S.
Bredt1
Departments of 1 Physiology and
2 Neurology, University of California, San Francisco, San
Francisco, California 94143
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, PSD95 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-95, 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 PSD95. Disrupting Hrs-regulated early endosomal sorting in hippocampal neurons selectively blocks synaptic clustering of PSD95 but does not interfere with trafficking of the palmitoylated isoform, PSD95 . 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.
Key words:
neuron; synapse; protein sorting; endosome; PSD95; Hrs
*
D.M.C. and R.C.B. contributed equally to this work
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156415-11$05.00/0
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