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  • Review Article
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Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density

Key Points

  • The postsynaptic density (PSD) of excitatory synapses is a membrane-associated mega-organelle that is highly enriched in glutamate receptors and their downstream signalling proteins. Scaffold proteins constitute a large proportion of PSD proteins and actively participate in trafficking, anchoring and clustering glutamate receptors; organizing multiple components into large signalling complexes; and interfacing with and regulating the dynamics of cytoskeletal structures.

  • Many PSD scaffold proteins are constructed from multiple copies of PDZ domains, which have self-oligomerization capacities. Each individual PDZ domain can bind to small peptide fragments situated at the very carboxyl tail of their targets. Therefore, multi-PDZ scaffold proteins are ideal for assembling large signalling complexes in synapses.

  • A feature of multi-PDZ-domain scaffold proteins is that two or more PDZ domains connected in tandem often show target-binding properties that are distinct from those of each isolated domain and even those of the simple sum of the isolated PDZ domains. Such structural and functional units of multiple PDZ domains are known as PDZ supramodules.

  • The supramodular nature of PDZ scaffold proteins, including PSD95, glutamate-receptor interacting protein 1 (GRIP1)–GRIP2, X11 (also known as APBA1 and MINT) and PAR3, originates from the direct interactions of PDZ domains connected in tandem. In addition to providing distinct target-binding properties, PDZ supramodules enable the dynamic regulation of scaffold proteins. As such, catalytically inactive scaffold proteins are not mere passive molecular 'glue'; rather, they can actively participate in the dynamic regulation of signalling events.

  • This supramodular nature is likely to be a common feature of many multidomain proteins in other cellular localizations besides the PSD. Given the findings discussed here, the structure and function of these proteins should be examined both at the individual and at the multiple-domain level.

Abstract

As the major components of the postsynaptic density of excitatory neuronal synapses, PDZ-domain-containing scaffold proteins regulate the clustering of surface glutamate receptors, organize synaptic signalling complexes, participate in the dynamic trafficking of receptors and ion channels, and coordinate cytoskeletal dynamics. These scaffold proteins often contain multiple PDZ domains, with or without other protein-binding modules, and they usually lack intrinsic enzymatic activities. Recent biochemical and structural studies have shown that tandemly arranged PDZ domains often serve as structural and functional supramodules that could regulate the organization and dynamics of synaptic protein complexes, thus contributing to the broad range of neuronal activity.

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Figure 1: Protein complex organization in the postsynaptic density (PSD).
Figure 2: Selected proteins containing supramodules.
Figure 3: Structure and target-binding properties of PDZ-domain supramodules.
Figure 4: PDZ supramodules as integrators of phospholipid and protein signalling.
Figure 5: The SH3–GK supramodules.
Figure 6: The DH–PH supramodules in RhoGEFs.

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GenBank/EMBL/DDBJ

Protein Data Bank

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Acknowledgements

We would like to apologize for not being able to cite many original papers from colleagues owing to space constraints. We thank N. Ip, J. Xia and members of M.Z.'s laboratory for comments and suggestions on the manuscript, and an anonymous reviewer for suggesting changes to figure 1. M.Z. is supported by grants from the Research Grants Council of Hong Kong.

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Glossary

Scaffold protein

A protein characterized by its multiple protein–protein interaction domains that can assemble multiple proteins, through individual domain-mediated interactions, into functional complexes in diverse cellular processes.

Adaptor protein

A protein that links protein components of signalling pathways, thereby aiding intracellular signal transduction. The terms 'adaptor protein' and 'scaffold protein' are sometimes used interchangeably in the literature.

Beads-on-a-string model

A model in which individual domains in multi-domain scaffold proteins are viewed as linearly connected globular folds with no direct contacts. According to the model, each domain functions independently.

Split protein domain

A protein domain that is characterized by insertions of one or several autonomously folded protein modules into the middle of the domain's primary sequence. In most split domains with known structures, the splitting does not normally change the domain's overall folding but often modifies its functions.

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Feng, W., Zhang, M. Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density. Nat Rev Neurosci 10, 87–99 (2009). https://doi.org/10.1038/nrn2540

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