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J. Cell Sci. 116 (15): 3213-3219


Research Article

Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks

Karen S. Christopherson1,2,*, Neal T. Sweeney1,3,*, Sarah E. Craven1,4, Rujun Kang5, Alaa El-Din El-Husseini1,5, and David S. Bredt1,{ddagger}

1 Department of Physiology University of California at San Francisco, San Francisco, CA 94143-2140, USA
* These authors contributed equally to this work

{ddagger} Author for correspondence (e-mail: bredt{at}itsa.ucsf.edu)

Accepted for publication 15 April 2003.

Abstract: 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.

Key Words: Synapse • Clustering • Receptor • Palmitoylation

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