Synaptic targeting of the postsynaptic density protein PSD-95 mediated by a tyrosine-based trafficking signal.
Synaptic function requires proper localization of proteins at synaptic sites. Targeting of the postsynaptic density protein 95 (PSD-95) relies on multiple signals within the protein, including twelve C-terminal amino acids. We now show that this C-terminal targeting domain of PSD-95 mediates postsynaptic localization through a short tyrosine-based motif followed by a pair of hydrophobic amino acids. Consistent with a role in cellular trafficking, the tyrosine motif resembles the canonical motif for interactions with clathrin adaptor proteins. In fact, we find that the C-terminal targeting domain of PSD-95 is sufficient to mediate clathrin-dependent endocytosis when appended to a transmembrane protein. Furthermore, systematic mutagenesis reveals that endocytosis mediated by this domain depends on both the tyrosine motif and the dihydrophobic amino acid pair. Thus, postsynaptic targeting of PSD-95 requires a tyrosine-based signal that can mediate clathrin-coated vesicle formation.
Craven
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Department of Physiology and Program in Neuroscience, University of California, San Francisco, San Francisco, California 94143-0444, USA.
Bredt
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D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004705:Endocytosis; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000737:chemistry* / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry*
D000596:Amino Acids; D002966:Clathrin; D018076:DNA, Complementary; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins; D049452:Green Fluorescent Proteins; D014443:Tyrosine