PDZ domain

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Molecular structure of the PDZ domain included in the human GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) protein
Identifiers
Symbol PDZ
Pfam PF00595
InterPro IPR001478
SMART PDZ
PROSITE PDOC50106
SCOP 1lcy
SUPERFAMILY 1lcy
CDD cd00136

The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses[1] and animals.[2] Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. PDZ is an acronym combining the first letters of three proteins — post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) — which were first discovered to share the domain.[3] PDZ domains have previously been referred to as DHR (Dlg homologous region)[4] or GLGF (glycine-leucine-glycine-phenylalanine) domains.[5] Proteins with these domains help hold together and organize signaling complexes at cellular membranes. Protein domains, connected by intrinsically disordered flexible linker regions, induce long-range allostery via protein domain dynamics.[6] PDZ domains also play a highly significant role in the anchoring of cell surface receptors (such as Cftr and FZD7) to the actin cytoskeleton via mediators like NHERF and ezrin. [7]

In general PDZ domains bind to a short region of the C-terminus of other specific proteins. These short regions bind to the PDZ domain by beta sheet augmentation. This means that the beta sheet in the PDZ domain is extended by the addition of a further beta strand from the tail of the binding partner protein.[8]

Origins of discovery

PDZ is an acronym derived from the names of the first proteins in which the domain was observed. Post-synaptic density protein 95 (PSD-95) is a synaptic protein found only in the brain[5] Drosophila disc large tumor suppressor (Dlg1) and zona occludens 1 (ZO-1) both play an important role at junctions and in cell signaling complexes.[9] Since the discovery of PDZ domains more than 20 years ago, researchers have successfully identified hundreds of PDZ domains. The first published use of the phrase “PDZ domain” was not in a paper, but a letter. In September 1995, Dr. Mary B. Kennedy of the California Institute of Technology wrote a letter of correction to Trends in Biomedical Sciences.[10] Earlier that year, another set of scientists had claimed to discover a new protein domain which they called a DHR domain.[11] Dr. Kennedy refuted that her lab had previously described exactly the same domain as a series of “GLGF repeats”.[5] She continued to explain that in order to “better reflect the origin and distribution of the domain,” the new title of the domain would be changed. Thus, the name “PDZ domain” was introduced to the world.

Functions

Any protein may have one or several PDZ domains, which can be identical or unique (see figure to right). Different PDZ domains can have different roles, each binding a different part of the target protein or a different protein altogether.[12] In this way, PDZ domains play a vital role in organizing and maintaining complex scaffolding formations.

File:PDZ figure 1.png
An example of a protein (GRIP) with seven PDZ domains.

PDZ domains are found in many different contexts and diverse proteins, but all assist in localization of cellular elements. PDZ domains are primarily involved in anchoring receptor proteins to the cytoskeleton. In any cell, an important responsibility is to get the right components—proteins and other molecules—in the right place at the right time. In the neuron, making sense of neurotransmitter activity requires specific receptors to be located in the lipid membrane at the synapse. PDZ domains are a critical part of this receptor localization process.[13] Proteins with PDZ domains generally associate with both the C-terminus of the receptor and cytoskeletal elements in order to anchor the receptor to the cytoskeleton and keep it in place.[12][14] Without such an interaction, receptors would diffuse out of the synapse due to the fluid nature of the lipid membrane.

PDZ domains are also utilized to localize elements other than receptor proteins. In the human brain, nitric oxide often acts in the synapse to modify cGMP levels in response to NMDA receptor activation.[15] In order to ensure a favorable spatial arrangements, neuronal nitric oxide synthase (nNOS) is brought close to NMDA receptors via interactions with PDZ domains on PSD-95, which concurrently binds nNOS and NMDA receptors.[14] With nNOS located closely to NMDA receptors, it will be activated immediately after calcium ions begin entering the cell. Instances such as this illustrate how PDZ domains can lead to greater signaling efficiency than diffusion alone.

Another interesting role played by PDZ domains involves regulation of the sorting pathway of endocytosed receptor proteins. A PDZ domain on the EBP50 protein binds to the C-terminus of the beta-2 adrenergic receptor (ß2-AR). EBP50 also associates with a complex that connects to actin, thus serving as a link between the cytoskeleton and ß2-AR.[16] The ß2-AR receptor is eventually endocytosed, where it will either be consigned to a lysosome for degradation or recycled back to the cell membrane. Scientists have demonstrated that when the Ser-411 residue of the ß2-AR PDZ binding domain, which interacts directly with EBP50, is phosphorylated, the receptor is degraded. If Ser-411 is left unmodified, the receptor is recycled.[16] The role played by PDZ domains and their binding sites indicate a regulative relevance beyond simply receptor protein localization.

PDZ proteins

Examples of PDZ domain-containing proteins (Figure from Lee et al. 2010).[17] Proteins are indicated by black lines scaled to the length of the primary sequence of the protein. Different shapes refer to different protein domains.

PDZ domains are found in many thousands of known proteins. PDZ domain proteins are widespread in eukaryotes and eubacteria,[2] whereas there are very few examples of the protein in archaea. PDZ domains are often associated with other protein domains and these combinations allow them to carry out their specific functions. Three of the most well documented PDZ proteins are PSD-95, GRIP, and HOMER. PSD-95 is a brain synaptic protein with three PDZ domains, each with unique properties and structures that allow PSD-95 to function in many ways. In general, the first two PDZ domains interact with receptors and the third interacts with cytoskeleton-related proteins. The main receptors associated with PSD-95 are NMDA receptors. The first two PDZ domains of PSD-95 bind to the C-terminus of NMDA receptors and anchor them in the membrane at the point of neurotransmitter release.[18] The first two PDZ domains can also interact in a similar fashion with Shaker-type K+ channels.[18] A PDZ interaction between PSD-95, nNOS and syntrophin is mediated by the second PDZ domain. The third and final PDZ domain links to cysteine-rich PDZ-binding protein (CRIPT), which allows PSD-95 to associate with the cytoskeleton.[18]

Glutamate receptor interacting protein (GRIP) is a post-synaptic protein with that interacts with AMPA receptors in a fashion analogous to PSD-95 interactions with NMDA receptors. When researchers noticed apparent structural homology between the C-termini of AMPA receptors and NMDA receptors, they attempted to determine if a similar PDZ interaction was occurring.[19] A yeast two-hybrid system helped them discover that out of GRIP’s seven PDZ domains, two (domains four and five) were essential for binding of GRIP to the AMPA subunit called GluR2.[12] This interaction is vital for proper localization of AMPA receptors, which play a large part in memory storage. Other researchers discovered that domains six and seven of GRIP are responsible for connecting GRIP to a family of receptor tyrosine kinases called ephrin receptors, which are important signaling proteins.[20] A clinical study concluded that Fraser syndrome, an autosomal recessive syndrome that can cause severe deformations, can be caused by a simple mutation in GRIP.[21]

HOMER differs significantly from many known PDZ proteins, including GRIP and PSD-95. Instead of mediating receptors near ion channels, as is the case with GRIP and PSD-95, HOMER is involved in metabotropic glutamate signaling.[7] Another unique aspect of HOMER is that it only contains a single PDZ domain, which mediates interactions between HOMER and type 5 metabotropic glutamate receptor (mGluR5).[13] The single GLGF repeat on HOMER binds amino acids on the C-terminus of mGluR5. HOMER expression is measured at high levels during embryologic stages in rats, suggesting an important developmental function.[13]

Human

There are roughly 260 human PDZ domains. However, several proteins contain multiple PDZ domains, so the number of unique PDZ-containing proteins is closer to 180. Listed below are some of the better studied members of this family:

Below is a complete list:

AAG12; AHNAK; AHNAK2; AIP1; ALP; APBA1; APBA2; APBA3; ARHGAP21; ARHGAP23; ARHGEF11; ARHGEF12; CASK; CLP-36; CNKSR2; CNKSR3; CRTAM; DFNB31; DLG1; DLG2; DLG3; DLG4; DLG5; DVL1; DVL1L1; DVL2; DVL3; ERBB2IP; FRMPD1; FRMPD2; FRMPD2L1; FRMPD3; FRMPD4; GIPC1; GIPC2; GIPC3; GOPC; GRASP; GRIP1; GRIP2; HTRA1; HTRA2; HTRA3; HTRA4; IL16; INADL; KIAA1849; LDB3; LIMK1; LIMK2; LIN7A; LIN7B; LIN7C; LMO7; LNX1; LNX2; LRRC7; MAGI1; MAGI2; MAGI3; MAGIX; MAST1; MAST2; MAST3; MAST4; MCSP; MLLT4; MPDZ; MPP1; MPP2; MPP3; MPP4; MPP5; MPP6; MPP7; MYO18A;  ;NOS1; PARD3; PARD3B; PARD6A; PARD6B; PARD6G; PDLIM1; PDLIM2; PDLIM3; PDLIM4; PDLIM5; PDLIM7; PDZD11; PDZD2; PDZD3; PDZD4; PDZD5A; PDZD7; PDZD8; PDZK1; PDZRN3; PDZRN4; PICK1; PPP1R9A; PPP1R9B; PREX1; PRX; PSCDBP; PTPN13; PTPN3; PTPN4; RAPGEF2; RAPGEF6; RGS12; RGS3; RHPN1; RIL; RIMS1; RIMS2; SCN5A; SCRIB; SDCBP; SDCBP2; SHANK1; SHANK2; SHANK3; SHROOM2; SHROOM3; SHROOM4; SIPA1; SIPA1L1; SIPA1L2; SIPA1L3; SLC9A3R1; SLC9A3R2; SNTA1; SNTB1; SNTB2; SNTG1; SNTG2; SNX27; SPAL2; STXBP4; SYNJ2BP; SYNPO2; SYNPO2L; TAX1BP3; TIAM1; TIAM2; TJP1; TJP2; TJP3; TRPC4; TRPC5; USH1C; WHRN;

Virus

Tax1

References

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  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 13.2 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ 14.0 14.1 Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ 16.0 16.1 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ 18.0 18.1 18.2 Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.

Further reading

  • Lua error in package.lua at line 80: module 'strict' not found.
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External links

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