Ks. Christopherson et al., PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain, J BIOL CHEM, 274(39), 1999, pp. 27467-27473
Nitric oxide (NO) biosynthesis in cerebellum is preferentially activated by
calcium influx through N-methyl-D-aspartate (NMDA)-type glutamate receptor
s, suggesting that there is a specific link between these receptors and neu
ronal NO synthase (nNOS). Here, we find that PSD-95 assembles a postsynapti
c protein complex containing nNOS and NMDA receptors. Formation of this com
plex is mediated by the PDZ domains of PSD-95, which bind to the COOH termi
ni of specific NMDA receptor subunits. In contrast, nNOS is recruited to th
is complex by a novel PDZ-PDZ interaction in which PSD-95 recognizes an int
ernal motif adjacent to the consensus nNOS PDZ domain. This internal motif
is a structured "pseudo-peptide" extension of the nNOS PDZ that interacts w
ith the peptide-binding pocket of PSD-95 PDZ2. This asymmetric interaction
leaves the peptide-binding pocket of the nNOS PDZ domain available to inter
act with additional COOH-terminal PDZ ligands. Accordingly, we find that th
e nNOS PDZ domain can bind PSD-95 PDZ2 and a COOH-terminal peptide simultan
eously. This bivalent nature of the nNOS PDZ domain further expands the sco
pe for assembly of protein networks by PDZ domains.