Trends in Cell Biology
ReviewPDZ domains in synapse assembly and signalling
Section snippets
What is a PDZ domain?
The PDZ domain was identified initially as a common element present in three structurally related proteins: PSD-95/SAP90, DLG and ZO1 (2, 3, 4). The PDZ domain has also been referred to as the DLG homology region (DHR) or the GLGF repeat, based on the presence of a Gly-Leu-Gly-Phe sequence motif. The PDZ domain, consisting of ∼90 amino acid residues, binds to short peptide sequences with 10–100 nm affinity2, 6. Most of these short peptide sequences are located on the C-terminal tails of the
PDZ-domain-containing proteins in the assembly of the PSD at glutamatergic synapses
In vertebrates, glutamatergic neurons provide the primary excitatory input within the central nervous system (CNS). Based on pharmacological, molecular and immunological criteria5, 13, three classes of multi-subunited ionotropic glutamate receptors have been characterized and localized at excitatory glutamatergic synapses. These include AMPA (dl-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, which mediate fast excitatory synaptic transmission; NMDA (N-methyl-d-aspartate)
The role of PDZ-domain-containing proteins in signal transduction at glutamatergic synapses
PDZ-domain-containing proteins also bind specifically to proteins involved in signal-transduction processes, suggesting that they might couple NMDA and AMPA receptors to downstream signalling pathways. The SAP90/PSD-95 family of proteins binds GTPase-activating proteins (GAPs) and GDP–GTP exchange factors (GEFs) that regulate the activity of the small G proteins ras and rho. For example, SAP90/PSD-95 and SAP102 bind to synGAP, a novel rasGAP found only at excitatory synapses that also contain a
Interactions between PDZ-domain-containing proteins and the membrane cytoskeleton of synapses
In addition to forming macromolecular signalling complexes, PDZ-domain-containing proteins interact with the synaptic cytoskeleton and cell-adhesion molecules (CAMs). Such interactions are probably important for the maintenance of synaptic structure and holding the neurotransmitter release and reception apparatus in close apposition. For example, the PDZ domains in SAP90/PSD-95 family members have been found to interact with the microtubule-associated protein CRIPT53, in addition to synaptic
PDZ-domain-containing proteins in the presynaptic cytoskeletal matrix
Although less well understood, PDZ-domain-containing proteins also seem to play a role in the assembly of the presynaptic active zone. As mentioned above, two members of the SAP90/PSD-95 family localize to the presynaptic nerve terminal. A second component is CASK54, a more distantly related MAGUK containing an N- terminal calmodulin (CaM) kinase-like domain, a veli-binding domain and a PDZ, an SH3 and a GK domain61 (Fig. 2). The PDZ domain of CASK binds to neurexin, providing a potential
PDZ domains and membrane trafficking
Several studies have indicated that PDZ-domain-containing proteins are important for the specific localization of proteins at synapses. However, the molecular mechanisms involved in this process are not clear. The regulation of the proper synaptic targeting of proteins could involve many steps, including the sorting, dendritic export, local insertion, local stabilization and aggregation, in addition to the endocytosis and recycling, of the proteins (Fig. 5). Recent studies in non-neuronal cells
Concluding remarks
Synapses in the CNS are exquisite molecular machines that are designed to transmit signals rapidly and efficiently from one neuron to the next. The presynaptic specialization responsible for the release of neurotransmitters is aligned precisely with the postsynaptic apparatus containing neurotransmitter receptors through an elaborate trans-synaptic protein complex (Fig. 4). Recent advances in the molecular characterization of synaptic junctions have revealed that the junctional complex is
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