Summary: PDZ domain (Also known as DHR or GLGF)
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PDZ domain Edit Wikipedia article
Molecular structure of the PDZ domain included in the human GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) protein
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. PDZ is an initialism combining the first letters of the first three proteins discovered to share the domain — post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1). PDZ domains have previously been referred to as DHR (Dlg homologous region) or GLGF (glycine-leucine-glycine-phenylalanine) domains. Proteins with these domains help hold together and organize signaling complexes at cellular membranes. These domains play a key role in the formation and function of signal transduction complexes. PDZ domains also play a highly significant role in the anchoring of cell surface receptors (such as Cftr[disambiguation needed] and FZD7) to the actin cytoskeleton via mediators like NHERF and ezrin.
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.
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. Drosophila disc large tumor suppressor (Dlg1) and zona occludens 1 (ZO-1) both play an important role at cell junctions and in cell signaling complexes. 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. Earlier that year, another set of scientists had claimed to discover a new protein domain which they called a DHR domain. Dr. Kennedy refuted that her lab had previously described exactly the same domain as a series of “GLGF repeats”. 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.
PDZ domain structure is not conserved across the various proteins that contain them, however there are similar trends seen in the PDZ domain. They usually have 4 β-strands and one short and one long α-helix. Apart from one fold that is conserved, the secondary structure is quite different across PDZ domain containing proteins. This domain tends to have a globular confirmation of about 35 Å.
When they are studied, PDZ domains are usually isolated into a monomer, however several studies have shown that some PDZ proteins form dimers. The function of PDZ protein dimers as compared to monomers is not yet known.
The commonly accepted theory for the binding pocket of many PDZ domains is that it is made up of several hydrophobic amino acids. Most PDZ domains only have one binding site located between one of the β-strands and the long α-helix.
PDZ domains have two main functions: Localizing cellular elements, and regulating cellular pathways.
The first discovered function of the PDZ domains was to anchor receptor proteins in the membrane to cytoskeletal components. PDZ domains also have regulatory functions on different signaling pathways. Any protein may have one or several PDZ domains, which can be identical or unique (see figure to right). This variety allows these proteins to be very versatile in their interactions. Different PDZ domains in the same protein can have different roles, each binding a different part of the target protein or a different protein altogether.
PDZ domains play a vital role in organizing and maintaining complex scaffolding formations, but this diversity in binding allows proteins with these domains to carry out a wide range of functions in this capacity.
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. For cells to function properly it is important for the right components—proteins and other molecules— to be in the right place at the right time. Proteins with PDZ domains are able to bind to different components to ensure that the correct arrangement is met. In the neuron, making sense of neurotransmitter activity requires specific receptors to be located in the lipid membrane at the synapse. PDZ domains are crucial to this receptor localization process. 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. 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. 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. With nNOS located closely to NMDA receptors, it will be activated immediately after calcium ions begin entering the cell.
PDZ domains are directly involved in the regulation of different cellular pathways. This mechanism of this regulation varies as PDZ domains are able to interact with a range of cellular components. This regulation is usually a result of the co-localization of multiple signaling molecules such as in the example with nNos and NMDA receptors. Some examples of signaling pathway regulation executed by the PDZ domain include phosphatase enzyme activity, mecahnosensory signaling, and the sorting pathway of endocytosed receptor proteins.
The signaling pathway of the human protein tyrosine phosphatase non-receptor type 4 (PTPN4) is regulated by PDZ domains. This protein is involved in regulating cell death. Normally the PDZ domain of this enzyme is unbound. In this unbound state the enzyme is active and prevents cell signaling for apoptosis. Binding the PDZ domain of this phosphatase results in a loss of enzyme activity, which leads to apoptosis. The normal regulation of this enzyme prevents cells from prematurely going through apoptosis. When the regulation of the PTPN4 enzyme is lost, there is increased oncogenic activity as the cells are able to proliferate.
PDZ domains also have a regulatory role in mechanosensory signaling in proprioceptors and vestibular and auditory hair cells. The protein Whirlin (WHRN) localizes in the post-synaptic neurons of hair cells that transform mechanical movement into action potentials that the body can interpret. WHRN proteins contains three PDZ domains. The domains located near the N-terminus bind to receptor proteins and other signaling components. When the one of these PDZ domains is inhibited, the signaling pathways of the neurons are disrupted, resulting in auditory, visual, and vestibular impairment. This regulation is thought to be based on the physical positioning WHRN and the selectivity of its PDZ domain.
Regulation of receptor proteins occurs when the 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. 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. The role played by PDZ domains and their binding sites indicate a regulative relevance beyond simply receptor protein localization.
PDZ domains are being studied further to better understand the role they play in different signaling pathways. Research has increased as these domains have been linked to different diseases including cancer as discussed above.
Regulation of PDZ domain activity
PDZ domain function can be both inhibited and activated by various mechanisms. Two of the most prevalent include allosteric interactions and posttraslational modifications.
The most common post-traslational modification seen on PDZ domains is phosphorylation. This modification is primarily an inhibitor of PDZ domain and ligand activity. In some examples, phosphorylation of amino acid side chains eliminates the ability of the PDZ domain to form hydrogen bonds, disrupting the normal binding patterns. The end result is a loss of PDZ domain function and further signaling. Another way phosphorylation can disrupt regualr PDZ domain funcition is by altering the charge ratio and further affecting binding and signaling. In rare cases researchers have seen post-translational modifications activate PDZ domain activity but these cases are few.
Another post-translational modification that can regulate PDZ domains is the formation of disulfide bridges. Many PDZ domains contain cysteines and are susceptible to disulfide bond formation in oxidizing conditions. This modification acts primarily as an inhibitor of PDZ domain function.
Protein-protein interactions have been observed to alter the effectiveness of PDZ domains binding to ligands. These studies show that allosteric effects of certain proteins can affect the binding affinity for different substrates. Different PDZ domains can even have this allosteric effect on each other. This PDZ-PDZ interaction only acts as an inhibitor. Other experiments have shown that certain enzymes can enhance the binding of PDZ domains. Researchers found that the protein ezrin enhances the binding of the PDZ protein NHERF1.
PDZ proteins are a family of proteins that contain the PDZ domain. This sequence of amino-acids is found in many thousands of known proteins. PDZ domain proteins are widespread in eukaryotes and eubacteria, 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. The first two PDZ domains can also interact in a similar fashion with Shaker-type K+ channels. 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.
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. 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. 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. 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.
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. 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). 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.
Human PDZ proteins
There are roughly 260 PDZ domains in humans. Several proteins contain multiple PDZ domains, so the number of unique PDZ-containing proteins is closer to 180. In the table below are some of the better studied members of this family:
|Studied PDZ Proteins|
The table below contains all known PDZ proteins in humans (alphabetical):
There is currently one known virus of PDZ domains:
- Boxus M, Twizere JC, Legros S, Dewulf JF, Kettmann R, Willems L (2008). "The HTLV-1 Tax interactome". Retrovirology. 5: 76. PMC . PMID 18702816. doi:10.1186/1742-4690-5-76.
- Ponting CP (February 1997). "Evidence for PDZ domains in bacteria, yeast, and plants". Protein Sci. 6 (2): 464–468. PMC . PMID 9041651. doi:10.1002/pro.5560060225.
- Kennedy MB (September 1995). "Origin of PDZ(DHR,GLGF) domains". Trends Biochem. Sci. 20 (9): 350. PMID 7482701. doi:10.1016/S0968-0004(00)89074-X.
- Ponting CP, Phillips C (March 1995). "DHR domains in syntrophins, neuronal NO synthases and other intracellular proteins". Trends Biochem. Sci. 20 (3): 102–103. PMID 7535955. doi:10.1016/S0968-0004(00)88973-2.
- Cho KO, Hunt CA, Kennedy MB (Nov 1992). "The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein". Neuron. 9 (5): 929–42. PMID 1419001. doi:10.1016/0896-6273(92)90245-9.
- Lee HJ, Zheng JJ (2010). "PDZ domains and their binding partners: structure, specificity, and modification". Cell Commun. Signal. 8: 8. PMC . PMID 20509869. doi:10.1186/1478-811X-8-8.
- Li, Jianquan; Callaway, David J.E.; Bu, Zimei (2009-09-11). "Ezrin induces long-range interdomain allostery in the scaffolding protein NHERF1". Journal of Molecular Biology. 392 (1): 166–180. ISSN 0022-2836. PMC . PMID 19591839. doi:10.1016/j.jmb.2009.07.005.
- Cowburn D (December 1997). "Peptide recognition by PTB and PDZ domains". Curr. Opin. Struct. Biol. 7 (6): 835–838. PMID 9434904. doi:10.1016/S0959-440X(97)80155-8.
- Liu, Jie; Li, Juan; Ren, Yu; Liu, Peijun (2014-01-01). "DLG5 in cell polarity maintenance and cancer development". International Journal of Biological Sciences. 10 (5): 543–549. ISSN 1449-2288. PMC . PMID 24910533. doi:10.7150/ijbs.8888.
- Kennedy, M. B. (1995-09-01). "Origin of PDZ (DHR, GLGF) domains". Trends in Biochemical Sciences. 20 (9): 350. ISSN 0968-0004. PMID 7482701. doi:10.1016/s0968-0004(00)89074-x.
- Ponting, Christopher P.; Phillips, Christopher (1995-03-01). "DHR domains in syntrophins, neuronal NO synthases and other intracellular proteins". Trends in Biochemical Sciences. 20 (3): 102–103. PMID 7535955. doi:10.1016/S0968-0004(00)88973-2.
- Erlendsson, Simon; Madsen, Kenneth Lindegaard (2015-10-16). "Membrane Binding and Modulation of the PDZ Domain of PICK1". Membranes. 5 (4): 597–615. ISSN 2077-0375. PMC . PMID 26501328. doi:10.3390/membranes5040597.
- Cabral, João H. Morais; Petosa, Carlo; Sutcliffe, Michael J.; Raza, Sami; Byron, Olwyn; Poy, Florence; Marfatia, Shirin M.; Chishti, Athar H.; Liddington, Robert C. (1996-08-15). "Crystal structure of a PDZ domain". Nature. 382 (6592): 649–652. doi:10.1038/382649a0.
- Harris, B. Z.; Lim, W. A. (2001-09-01). "Mechanism and role of PDZ domains in signaling complex assembly". Journal of Cell Science. 114 (Pt 18): 3219–3231. ISSN 0021-9533. PMID 11591811.
- Bristol, University of. "Bristol University | Centre for Synaptic Plasticity | AMPAR interactors". www.bristol.ac.uk. Retrieved 2015-12-03.
- Brakeman, P. R.; Lanahan, A. A.; O'Brien, R.; Roche, K.; Barnes, C. A.; Huganir, R. L.; Worley, P. F. (1997-03-20). "Homer: a protein that selectively binds metabotropic glutamate receptors". Nature. 386 (6622): 284–288. ISSN 0028-0836. PMID 9069287. doi:10.1038/386284a0.
- Doyle, Declan A.; Lee, Alice; Lewis, John; Kim, Eunjoon; Sheng, Morgan; MacKinnon, Roderick (1996-06-28). "Crystal Structures of a Complexed and Peptide-Free Membrane Protein–Binding Domain: Molecular Basis of Peptide Recognition by PDZ". Cell. 85 (7): 1067–1076. PMID 8674113. doi:10.1016/S0092-8674(00)81307-0.
- Hopper, Rachel; Lancaster, Barrie; Garthwaite, John (2004-04-01). "On the regulation of NMDA receptors by nitric oxide". European Journal of Neuroscience. 19 (7): 1675–1682. ISSN 1460-9568. PMID 15078541. doi:10.1111/j.1460-9568.2004.03306.x.
- Maisonneuve, Pierre; Caillet-Saguy, Célia; Raynal, Bertrand; Gilquin, Bernard; Chaffotte, Alain; Pérez, Javier; Zinn-Justin, Sophie; Delepierre, Muriel; Buc, Henri (2014-11-01). "Regulation of the catalytic activity of the human phosphatase PTPN4 by its PDZ domain". FEBS Journal. 281 (21): 4852–4865. ISSN 1742-4658. doi:10.1111/febs.13024.
- Nooij, Joriene C. de; Simon, Christian M.; Simon, Anna; Doobar, Staceyann; Steel, Karen P.; Banks, Robert W.; Mentis, George Z.; Bewick, Guy S.; Jessell, Thomas M. (2015-02-18). "The PDZ-Domain Protein Whirlin Facilitates Mechanosensory Signaling in Mammalian Proprioceptors". Journal of Neuroscience. 35 (7): 3073–3084. ISSN 0270-6474. PMC . PMID 25698744. doi:10.1523/JNEUROSCI.3699-14.2015.
- Cao, Tracy T.; Deacon, Heather W.; Reczek, David; Bretscher, Anthony; von Zastrow, Mark (1999-09-16). "A kinase-regulated PDZ-domain interaction controls endocytic sorting of the β2-adrenergic receptor". Nature. 401 (6750): 286–290. ISSN 0028-0836. PMID 10499588. doi:10.1038/45816.
- Wang, Nick X.; Lee, Ho-Jin; Zheng, Jie (2016-11-29). "Therapeutic use of PDZ protein-protein interaction antagonism". Drug news & perspectives. 21 (3): 137–141. ISSN 0214-0934. PMC . PMID 18560611.
- Chung, Hee Jung; Huang, Yan Hua; Lau, Lit-Fui; Huganir, Richard L. (2004-11-10). "Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand". The Journal of Neuroscience. 24 (45): 10248–10259. ISSN 1529-2401. PMID 15537897. doi:10.1523/JNEUROSCI.0546-04.2004.
- Jeleń, Filip; Oleksy, Arkadiusz; Smietana, Katarzyna; Otlewski, Jacek (2003-01-01). "PDZ domains - common players in the cell signaling". Acta Biochimica Polonica. 50 (4): 985–1017. ISSN 0001-527X. PMID 14739991.
- Chen, Jia; Pan, Lifeng; Wei, Zhiyi; Zhao, Yanxiang; Zhang, Mingjie (2008-08-06). "Domain-swapped dimerization of ZO-1 PDZ2 generates specific and regulatory connexin43-binding sites". The EMBO Journal. 27 (15): 2113–2123. ISSN 1460-2075. PMC . PMID 18636092. doi:10.1038/emboj.2008.138.
- Chen, Bo-Shiun; Braud, Stephanie; Badger, John D.; Isaac, John T. R.; Roche, Katherine W. (2006-06-16). "Regulation of NR1/NR2C N-methyl-D-aspartate (NMDA) receptors by phosphorylation". The Journal of Biological Chemistry. 281 (24): 16583–16590. ISSN 0021-9258. PMID 16606616. doi:10.1074/jbc.M513029200.
- Mishra, Prashant; Socolich, Michael; Wall, Mark A.; Graves, Jennifer; Wang, ZiFen; Ranganathan, Rama (2007-10-05). "Dynamic scaffolding in a G protein-coupled signaling system". Cell. 131 (1): 80–92. ISSN 0092-8674. PMID 17923089. doi:10.1016/j.cell.2007.07.037.
- van den Berk, Lieke C. J.; Landi, Elena; Walma, Tine; Vuister, Geerten W.; Dente, Luciana; Hendriks, Wiljan J. A. J. (2007-11-27). "An allosteric intramolecular PDZ-PDZ interaction modulates PTP-BL PDZ2 binding specificity". Biochemistry. 46 (47): 13629–13637. ISSN 0006-2960. PMID 17979300. doi:10.1021/bi700954e.
- Niethammer, M.; Valtschanoff, J. G.; Kapoor, T. M.; Allison, D. W.; Weinberg, R. J.; Craig, A. M.; Sheng, M. (1998-04-01). "CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90". Neuron. 20 (4): 693–707. ISSN 0896-6273. PMID 9581762. doi:10.1016/s0896-6273(00)81009-0.
- Dong, H.; O'Brien, R. J.; Fung, E. T.; Lanahan, A. A.; Worley, P. F.; Huganir, R. L. (1997-03-20). "GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors". Nature. 386 (6622): 279–284. ISSN 0028-0836. PMID 9069286. doi:10.1038/386279a0.
- Torres, Richard; Firestein, Bonnie L; Dong, Hualing; Staudinger, Jeff; Olson, Eric N; Huganir, Richard L; Bredt, David S; Gale, Nicholas W; Yancopoulos, George D (1998-12-01). "PDZ Proteins Bind, Cluster, and Synaptically Colocalize with Eph Receptors and Their Ephrin Ligands". Neuron. 21 (6): 1453–1463. PMID 9883737. doi:10.1016/S0896-6273(00)80663-7.
- Vogel, Maartje J.; van Zon, Patrick; Brueton, Louise; Gijzen, Marleen; van Tuil, Marc C.; Cox, Phillip; Schanze, Denny; Kariminejad, Ariana; Ghaderi-Sohi, Siavash (2012-05-01). "Mutations in GRIP1 cause Fraser syndrome". Journal of Medical Genetics. 49 (5): 303–306. ISSN 1468-6244. PMID 22510445. doi:10.1136/jmedgenet-2011-100590.
- Ranganathan R, Ross E (1997). "PDZ domain proteins: scaffolds for signaling complexes". Curr Biol. 7 (12): R770–R773. PMID 9382826. doi:10.1016/S0960-9822(06)00401-5.
- Jemth P, Gianni S (July 2007). "PDZ domains: folding and binding". Biochemistry. 46 (30): 8701–8708. PMID 17620015. doi:10.1021/bi7008618.
- Ponting CP, Phillips C, Davies KE, Blake DJ (June 1997). "PDZ domains: targeting signalling molecules to sub-membranous sites". BioEssays. 19 (6): 469–479. PMID 9204764. doi:10.1002/bies.950190606.
- Doyle DA, Lee A, Lewis J, Kim E, Sheng M, MacKinnon R (June 1996). "Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ". Cell. 85 (7): 1067–1076. PMID 8674113. doi:10.1016/S0092-8674(00)81307-0.
- Eukaryotic Linear Motif resource motif class LIG_PDZ_Class_1
- Eukaryotic Linear Motif resource motif class LIG_PDZ_Class_2
- Eukaryotic Linear Motif resource motif class LIG_PDZ_Class_3
- The PDZ Domain as a Complex Adaptive System A concise technical summary and a statement of principal findings and ramifications of the PDZ Domain as a Complex Adaptive System
- NCBI conserved domains entry
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
PDZ domain (Also known as DHR or GLGF) Provide feedback
PDZ domains are found in diverse signaling proteins.
Doyle DA, Lee A, Lewis J, Kim E, Sheng M, MacKinnon R; , Cell. 1996;85:1067-1076.: Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. PUBMED:8674113 EPMC:8674113
Ernst A, Sazinsky SL, Hui S, Currell B, Dharsee M, Seshagiri S, Bader GD, Sidhu SS;, Sci Signal. 2009;2:ra50.: Rapid evolution of functional complexity in a domain family. PUBMED:19738200 EPMC:19738200
Internal database links
|SCOOP:||GRASP55_65 PDZ_1 PDZ_2 Peptidase_M50 Tricorn_PDZ|
|Similarity to PfamA using HHSearch:||Peptidase_M50 PDZ_2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001478
PDZ domains (also known as Discs-large homologous regions (DHR) or GLGF)) are found in diverse signalling proteins in bacteria, yeasts, plants, insects and vertebrates [PUBMED:9041651, PUBMED:9204764]. PDZ domains can occur in one or multiple copies and are nearly always found in cytoplasmic proteins. They bind either the carboxyl-terminal sequences of proteins or internal peptide sequences [PUBMED:9204764]. In most cases, interaction between a PDZ domain and its target is constitutive, with a binding affinity of 1 to 10 microns. However, agonist-dependent activation of cell surface receptors is sometimes required to promote interaction with a PDZ protein. PDZ domain proteins are frequently associated with the plasma membrane, a compartment where high concentrations of phosphatidylinositol 4,5-bisphosphate (PIP2) are found. Direct interaction between PIP2 and a subset of class II PDZ domains (syntenin, CASK, Tiam-1) has been demonstrated.
PDZ domains consist of 80 to 90 amino acids comprising six beta-strands (beta-A to beta-F) and two alpha-helices, A and B, compactly arranged in a globular structure. Peptide binding of the ligand takes place in an elongated surface groove as an anti-parallel beta-strand interacts with the beta-B strand and the B helix. The structure of PDZ domains allows binding to a free carboxylate group at the end of a peptide through a carboxylate-binding loop between the beta-A and beta-B strands.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||protein binding (GO:0005515)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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We make a range of alignments for each Pfam-A family:
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||44|
|Number in full:||38522|
|Average length of the domain:||80.80 aa|
|Average identity of full alignment:||24 %|
|Average coverage of the sequence by the domain:||15.77 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 26 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PDZ domain has been found. There are 950 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...