By definition, scaffolds have the function of assembling a complex of proteins that bind to their concatenated protein-protein interaction domains. At CNS excitatory synapses, each glutamate receptor subclass is associated with a complex of different and often interconnected scaffold proteins. The first scaffold proteins identified as being associated with glutamate receptors were PSD-95 for the NMDA receptor, GRIP for AMPA receptors, and Homer for metabotropic GluRs (mGluRs) (Figure 18.2; Colorplate 11)13. One of the first observations made in those early days was that most of these proteins have a PDZ domain. We will discuss PSD-95 and Homer function in detail later, and here concentrate on the function of the PDZ domain and the complex of scaffold proteins interacting with AMPA-type receptors.
PDZ domain-containing proteins play a central role at the synapses, as is shown by the fact that several synaptic scaffold proteins contain at least one PDZ domain (for a review, see 14). The major function of these PDZ-containing proteins is to act as scaffolds for the assembly of large protein complexes at specific subcellular locations, particularly on the cell surface. The PDZ functions as a modular domain that is well suited to be inserted into multi-PDZ proteins, or combined with other modular protein interaction domains in order to generate more complex scaffolds. Most PDZ domains recognize a few amino acids at the C-termini of proteins, and thus interact with the large majority of transmembrane proteins whose C-termini face the cytoplasm, as in the case of all glutamate receptors. It is therefore not surprising that PDZ proteins are well suited for postsynaptic membrane functions. It is also important to note that PDZ domains have different binding specificities, which means that the combination of different PDZ domains within a scaffold protein determines the composition of the protein complex assembled around the scaffold. Finally, most PDZ-containing proteins can multimerize to increase the size and, potentially, the heterogeneity of the PDZ-based complex15.
One clear example of the synaptic function of PDZ-containing scaffold proteins came from studies of the mechanisms that modulate the synaptic trafficking of AMPA-type glutamate receptors. The number of synaptic AMPA receptors directly regulates synapse potentiation and depression, which are respectively associated with LTP and long-term depression (LTD). AMPA receptors are linked to two major scaffold proteins, the glutamate-receptor-interacting protein/AMPAR-binding protein (GRIP/ABP, encoded by the two distinct genes GRIP1 and ABP/GRIP2), and the protein interacting with C kinase 1 (PICK1); these interactions may account for the dynamic cell-biological behavior of AMPARs at synapses.
The C-terminal of the GluR2/3 subunit specifically binds to the PDZ5 domain of GRIP, but the PDZ4 domain is also required for a strong interaction by stabilizing the PDZ5 structure through interdomain interactions16. GRIP is believed to be involved in the synaptic trafficking and/or stabilization of AMPARs and other interacting proteins (also see Chapter 24). The widespread cellular distribution of GRIP and its interaction with motor proteins [directly with conventional kinesin KIF517 or indirectly with KIF1A via liprin-a18] suggest that multiple motor proteins may contribute to the transport of AMPARs.
GRIP has up to seven PDZ domains through which it can interact with many proteins, including Eph receptors and their ephrin ligands19, a RAS guanine nucleotide exchange factor (RasGEF)20, liprin- a21, the transmembrane protein Fraser syndrome 1 (FRAS1)22, and the metabotropic and kainate-type glutamate receptors23. Thus GRIP can participate in synaptic function not only by interacting with AMPARs, but also by associating with Eph receptors and their ephrin ligands, which have been found to be involved in dendrites and dendritic spine morphogenesis and hippocampal synaptic plasticity24,25.
PICK1 is located at synaptic and nonsynaptic sites in neurons. Its PDZ domain has relatively promiscuous binding properties, and both pre- and postsynaptic partners have been found: PKCa, GluR2/3, the netrin receptor UNC5H26, various metabotropic glutamate receptor subtypes27'28, the dopamine plasma-membrane transporter29, and the erythroblastic leukemia viral oncogene homolog 2 (ErbB2) receptor tyrosine kinase30. In most of these cases, the subcellular localization and/or surface expression of these partners seems to be regulated by interactions with PICK1.
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