Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs

Neuron. 1999 Mar;22(3):497-509. doi: 10.1016/s0896-6273(00)80705-9.

Abstract

During synaptic development, proteins aggregate at specialized pre- and postsynaptic structures. Mechanisms that mediate protein clustering at these sites remain unknown. To investigate this process, we analyzed synaptic targeting of a postsynaptic density protein, PSD-95, by expressing green fluorescent protein- (GFP-) tagged PSD-95 in cultured hippocampal neurons. We find that postsynaptic clustering relies on three elements of PSD-95: N-terminal palmitoylation, the first two PDZ domains, and a C-terminal targeting motif. In contrast, disruptions of PDZ3, SH3, or guanylate kinase (GK) domains do not affect synaptic targeting. Palmitoylation is sufficient to target the diffusely expressed SAP-97 to synapses, and palmitoylation cannot be replaced with alternative membrane association motifs, suggesting that a specialized synaptic lipid environment mediates postsynaptic clustering. The requirements for PDZ domains and a C-terminal domain of PSD-95 indicate that protein-protein interactions cooperate with lipid interactions in synaptic targeting.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cloning, Molecular
  • Disks Large Homolog 4 Protein
  • Fluorescent Antibody Technique
  • Green Fluorescent Proteins
  • Guanylate Kinases
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Intracellular Signaling Peptides and Proteins
  • Lipid Metabolism
  • Lipids / physiology*
  • Luminescent Proteins / genetics
  • Membrane Proteins
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Neuronal Plasticity / physiology
  • Neurons / metabolism
  • Neurons / physiology*
  • Palmitic Acid / metabolism
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synapses / metabolism
  • Synapses / physiology*
  • Transfection
  • Tumor Suppressor Proteins

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • Luminescent Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • postsynaptic density proteins
  • Green Fluorescent Proteins
  • Palmitic Acid
  • DLG2 protein, human
  • Guanylate Kinases