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  • Review Article
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PDZ domain proteins of synapses

Nature Reviews Neuroscience volume 5, pages 771–781 (2004)Cite this article

Key Points

  • PDZ domains are modular protein-interaction domains that are specialized for binding to C-terminal peptide motifs of other proteins. PDZ-domain-based scaffolds typically assemble large molecular complexes at specific subcellular sites, such as synapses.

  • The postsynaptic density (PSD) of brain excitatory synapses contains many PDZ proteins, of which PSD-95 is the best characterized.

  • PSD-95 contains multiple domains that mediate its association with various membrane proteins (receptors, ion channels and cell-adhesion molecules) and cytoplasmic signalling molecules. PSD-95 influences the activity of interacting membrane proteins by controlling their surface delivery, stability, subcellular location, subunit composition and even intrinsic functional properties. By linking them with cytoplasmic signal transduction proteins, PSD-95 facilitates the functional coupling of postsynaptic receptors and ion channels to downstream signalling pathways involving nitric oxide, Ras, Rap and Rac.

  • Molecular genetic manipulations of PSD-95 in culture and in vivo have strong effects on synaptic transmission and plasticity. The abundance and activity of PSD-95 at synapses is dynamically controlled by activity, palmitoylation (lipid modification), degradation and phosphorylation.

  • The four members of the PSD-95 family of proteins show distinct patterns of palmitoylation, subcellular localization, temporal expression and binding partners, which presumably underlie their differential functions in synapses and neurons.

  • Genetic studies have revealed the in vivo functions of PSD-95 family scaffolds. In addition to learning and memory, PSD-95 family proteins are now implicated in the organization of cholinergic synapses, visual processing, pain perception and behavioural responses to drugs of abuse.

  • GRIP/ABP and PICK1 are PDZ proteins that bind directly to AMPA receptors and regulate their trafficking. With seven PDZ domains, GRIP interacts with numerous proteins, some of which (such as Eph receptors) might also regulate synaptic function. PICK1 also binds to a variety of membrane and cytoplasmic proteins, including kainate receptors.

  • PDZ scaffolds function in motor trafficking of their associated protein complexes. Several PDZ proteins bind directly to motor proteins of the kinesin and myosin families. In this way, PDZ scaffolds on the surface of vesicles can act as 'receptors', linking motors with their specific cargoes.

  • PDZ-based interactions are post-translationally regulated to allow controlled assembly or disassembly of synaptic protein complexes. For instance, AMPA-receptor interactions with GRIP are disrupted by phosphorylation of the C-terminal peptide of GluR2, which is correlated with internalization of AMPA receptors and synaptic depression.

  • With increasing knowledge of the structure and in vivo functions of synaptic PDZ proteins, PDZ interactions could become plausible targets for pharmaceutical intervention, thereby opening up a wealth of possibilities for the treatment of brain diseases.

Abstract

PDZ domains are protein-interaction domains that are often found in multi-domain scaffolding proteins. PDZ-containing scaffolds assemble specific proteins into large molecular complexes at defined locations in the cell. In the postsynaptic density of neuronal excitatory synapses, PDZ proteins such as PSD-95 organize glutamate receptors and their associated signalling proteins and determine the size and strength of synapses. PDZ scaffolds also function in the dynamic trafficking of synaptic proteins by assembling cargo complexes for transport by molecular motors. As key organizers that control synaptic protein composition and structure, PDZ scaffolds are themselves highly regulated by synthesis and degradation, subcellular distribution and post-translational modification.

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Figure 1: Three-dimensional structure of PDZ domains.
Figure 2: Schematic diagram of PDZ proteins.
Figure 3: A schematic diagram of the organization of PDZ proteins at a mammalian excitatory synapse.

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Acknowledgements

We thank Feng Wei and Mingjie Zhang (Hong Kong University of Science and Technology) for providing the PDZ domain structures for figure 1.

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Authors and Affiliations

  1. National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Guseong-dong, Yuseong-gu, 305-701, Daejeon, Korea

    Eunjoon Kim

  2. The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue (E18-215), Cambridge, 02139, Massachusetts, USA

    Morgan Sheng

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  1. Eunjoon Kim
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DATABASES

Entrez Gene

CASK

CDK5

Dlg

ErbB2

GKAP

GluR1

Homer

PICK1

PSD-95

SAP97

Shank

SPAR

Src

syndecan

FURTHER INFORMATION

Encyclopedia of Life Sciences

AMPA receptors

Dendritic spines

Long-term depression and depotentiation

Long-term potentiation

NMDA receptors

Glossary

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).

POSTSYNAPTIC DENSITY

An electron-dense specialization of excitatory postsynaptic membranes that contains a high concentration of glutamate receptors and associated signalling and cytoskeletal proteins.

SRC HOMOLOGY 3 DOMAIN

(SH3 domain). A protein–protein interaction domain that binds to PXXP or related peptide sequences.

GUANYLATE KINASE-LIKE DOMAIN

(GK domain). A protein–protein interaction domain found in the membrane-associated guanylate kinase (MAGUK) superfamily of proteins, which includes PSD-95 and related proteins.

RAS, RAP AND RAC

Small monomeric G-proteins that, in their activated GTP-bound state, interact with and stimulate their downstream effectors. Hydrolysis of bound GTP by the intrinsic GTPase activity of these proteins terminates their activity. Guanine nucleotide exchange factors (GEFs) stimulate GTP loading and activate these small G-proteins; GTPase-activating proteins (GAPs) inhibit their activity.

LONG-TERM POTENTIATION

(LTP). A long-lasting enhancement of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, high frequency tetanus). Typically dependent on NMDA-receptor activation, and widely believed to be a means of information storage in the brain.

DENDRITIC SPINES

Tiny actin-rich protrusions from the dendrite that form the postsynaptic compartment for most excitatory synapses in the brain.

RNA INTERFERENCE

(RNAi). A method for suppressing the expression of a specific protein based on targeted hybridization of small interfering RNAs to the mRNA encoding that protein.

LONG-TERM DEPRESSION

(LTD). A long-lasting suppression of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, low frequency stimulation). Typically dependent on NMDA-receptor activation, and widely believed to be a means of information storage in the brain.

KINESINS

A large family of structurally related motor proteins that use ATP to transport specific cargoes along microtubules.

MYOSINS

A large family of structurally related motor proteins that use ATP to transport specific cargoes along actin filaments.

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Kim, E., Sheng, M. PDZ domain proteins of synapses. Nat Rev Neurosci 5, 771–781 (2004). https://doi.org/10.1038/nrn1517

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