Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks.
Postsynaptic density protein 95 (PSD-95/SAP-90) is a palmitoylated membrane-associated guanylate kinase that oligomerizes and clusters ion channels and associated signaling machinery at excitatory synapses in brain. However, the mechanism for PSD-95 oligomerization and its relationship to ion channel clustering remain uncertain. Here, we find that multimerization of PSD-95 is determined by only its first 13 amino acids, which also have a remarkable capacity to oligomerize heterologous proteins. Multimerization does not involve a covalent linkage but rather palmitoylation of two cysteine residues in the 13 amino acid motif. This lipid-mediated oligomerization is a specific property of the PSD-95 motif, because it is not observed with other palmitoylated domains. Clustering K+ channel Kv1.4 requires interaction of palmitoylated PSD-95 with tetrameric K+ channel subunits but, surprisingly, does not require multimerization of PSD-95. Finally, disrupting palmitoylation with 2-bromopalmitate disperses PSD-95/K+-channel clusters. These data suggest new models for K+ channel clustering by PSD-95 - a reversible process regulated by protein palmitoylation.
Christopherson
Karen S
KS
Department of Physiology University of California at San Francisco, San Francisco, CA 94143-2140, USA.
Sweeney
Neal T
NT
Craven
Sarah E
SE
Kang
Rujun
R
El-Husseini
Alaa El-Din
Ael-D
Bredt
David S
DS
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D050356:Lipid Metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology
D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C033652:postsynaptic density proteins