Jump to content

User:Theyellowdart22/sandbox

From Wikipedia, the free encyclopedia

Edits to include in WIKI:

  • Something about associations of diff. PDZ domains in relation to AMPA and NMDA (GRIP is non-NMDA, PSD-95 is NMDA, HOMER is GPCR receptors). Find citations
  • Modify first section to be more clear (ie. anchor transmembrane proteins to cytoskeleton).

Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components.

Ideas for Paper:

  • Background on classification
  • Importance to the cell
  • Current research (primary)
  • Further research

Reference papers:

  1. A structural portrait of the PDZ domain family http://www.ncbi.nlm.nih.gov/pubmed/25158098'
  2. http://www.sciencedirect.com/science/article/pii/S0960982206004015
  3. Peptide bonding properties of the three PDZ domains of the bazooka http://www.ncbi.nlm.nih.gov/pubmed/25158884
  4. PDZ domain in the Engineering and Production of a Saporin chimeric toxin as a tool for targetting cancer skills http://www.ncbi.nlm.nih.gov/pubmed/25581839
  5. Roles of the PDZ domain-binding motif of the human papillomavirus type 16 E6 on the immortalization and differentiation of primary human foreskin keratinocytes. http://www.ncbi.nlm.nih.gov/pubmed/24293186

Rough Draft: The following is a rough draft of my review paper. I think I'll pick a paragraph or two from this for the PDZ domain article. Any suggestions would be helpful! I haven't included any citations yet, though I have them. Any general suggestions about additional info that might be nice to include are appreciated. Also, if something seems redundant, let me know!

History

One of the first published uses 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 (cite other paper). Dr. Kennedy refuted that her lab had previously described the exact 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 doain” was introduced to the world (cite her stuff).

Function

PDZ domains are found in many different contexts and diverse proteins. All PDZ domains assist in localization of cellular elements. In any cell, an important responsibility is to get the right components (proteins and other molecules) in the right place at the right time. For example, in the neuron, making sense of extracellular signals requires specific receptors to be located in the lipid membrane at the synapse. PDZ domains are a critical part of this receptor localization process (cite homer paper). Proteins with PDZ domains generally associate with the carboxyl-terminal of the receptor (see figure?) and cytoskeletal elements in order to anchor the receptor to the cytoskeleton and keep it in place (cite several probably). Without this 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 besides receptor proteins. In the human brain, nitric oxide often acts in the synapse to modify cGMP levels in response to NMDA receptor activation (http://www.ncbi.nlm.nih.gov/pubmed/15078541). 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 both PSD-95 and syntrophin (cite Crystal Structures). 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. One example involves the beta-2 adrenergic receptor (β2-AR). The PDZ domain on the EBP50 protein binds to the c-terminus of the beta-2 adrenergic receptor. EBP50 also associates with a complex that connects to actin, thus serving as a link between the cytoskeleton and β2-AR. These receptors are eventually endocytosed, where they 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 β2-AR PDZ binding domain is phosphorylated, the receptor is degraded. If Ser-411 is left unmodified, the receptor is recycled. (CITE Alder paper).   This example illustrates the importance that PDZ domains and their binding sites have in regulating receptor protein activity beyond simply holding them in place.

Common PDZ domains

Over 100 proteins have been identified with PDZ domains. 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 (cite). The first two PDZ domains also interact in a similar fashion with Shaker-type K+ channels (cite). The 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. (http://www.sciencedirect.com/science/article/pii/S0896627300810090).

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 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 led them to discover that out of GRIP’s seven PDZ domains, two (domains four and five) were essential for binding of GRIP to GluR2 (AMPA subunit) (cite). This interaction is vital for proper localization of AMPA receptors, which play a large part in memory storage. Others discovered that domains six and seven are responsible for connecting GRIP to a family of receptor tyrosine kinases called ephrin receptors, which are important signaling proteins (cite ephrin paper). 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 (cite fraser paper). This sentence is a little awkward maybe rephrase it? Rincrate (talk) 04:02, 9 December 2015 (UTC)

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.

PDZ proteins provide cells with a significant advantage in signaling efficiency. Their primary function is to anchor receptor proteins to cytoskeletal components. Without selective PDZ domains to maintain the localization of receptors, diffusion would lead to severely decreased response to neurotransmitter. In addition to binding receptors, PDZ domains take part in specific binding of regulatory enzymes and cytoskeletal proteins. PDZ proteins contain one or more PDZ domains, which each participating in one or more functions. Much is currently understood about some PDZ proteins such as PSD-95, GRIP and HOMER. However, further research in PDZ domains will yield a greater understanding of synaptic transmission and the mechanisms of membrane activity. 


      • I really like what you have written. I think it flows really well and simplifies a very complex subject to the point that it acts a quick, simple read in an encyclopedia. I fixed a few grammatical and spelling errors, but I did not note them specifically. One thing that I think I might change is the history section. It feels like it is too short to warrant its own section and sublink which is what it appears like you are doing. What I might do is either amplify the history with a little more information or combine tha brief history that you have with an introductory sentence or two about PDZ domains and have that act as the introductory paragraph to the article. Does that make sense? Anyway, it was just a thought. Overall, I think it is very well written. You nailed it! Great job! Skcirdnehat (talk) 12:52, 16 November 2015 (UTC)
      • it looks good! I made a couple changes to make a couple sentences flow better. I read both the article below and this one. Maybe add a little more to the history and the background of the PDZ domain for the article above. But if your most recently written article is below, I would say its good enough! I also made a couple changes to the article below too. It is simple to follow and it flows really well. Good job. Rincrate (talk) 04:32, 9 December 2015 (UTC)

Origins of Discovery

[edit]

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.3 Drosophila disc large tumor suppressor (Dlg1) and zona occludens 1 (ZO-1) both play an important role at junctions and in cell signaling complexes[1]. 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[2]. Earlier that year, another set of scientists had claimed to discover a new protein domain which they called a DHR domain[3]. Dr. Kennedy refuted that her lab had previously described the exact same domain as a series of “GLGF repeats”[4].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

[edit]

Any one protein may have one or several PDZ domains, which can be identical or unique (see figure).  Different PDZ domains can have different roles, each binding a different part of the target protein or a different protein altogether[5]. In this way, PDZ domains play a vital role in organizing and maintaining complex scaffolding formations.

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[6]. Proteins with PDZ domains generally associate with the C-terminus of the receptor (Figure 1) and cytoskeletal elements in order to anchor the receptor to the cytoskeleton and keep it in place[7][5]. 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[8]. 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[7]. 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[9]. 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[9]. The role played by PDZ domains and their binding sites indicate a regulative relevance beyond simply receptor protein localization.

Proteins containing this domain

[edit]

PDZ domains are found in many thousands of known proteins. PDZ domain proteins are widespread in eukaryotes and eubacteria,[10] however, 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[11]. The first two PDZ domains can also interact in a similar fashion with Shaker-type K+ channels[11]. 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[11].

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[5]. 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[12]. 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[13].

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[14]. 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)[6]. 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[6].

  1. ^ 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. doi:10.7150/ijbs.8888. ISSN 1449-2288. PMC 4046881. PMID 24910533.
  2. ^ Kennedy, M. B. (1995-09-01). "Origin of PDZ (DHR, GLGF) domains". Trends in Biochemical Sciences. 20 (9): 350. ISSN 0968-0004. PMID 7482701.
  3. ^ 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. doi:10.1016/S0968-0004(00)88973-2.
  4. ^ Cho, K. O.; Hunt, C. A.; Kennedy, M. B. (1992-11-01). "The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein". Neuron. 9 (5): 929–942. ISSN 0896-6273. PMID 1419001.
  5. ^ a b c Bristol, University of. "Bristol University | Centre for Synaptic Plasticity | AMPAR interactors". www.bristol.ac.uk. Retrieved 2015-12-03.
  6. ^ a b c 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. doi:10.1038/386284a0. ISSN 0028-0836. PMID 9069287.
  7. ^ a b Doyle, D. A.; Lee, A.; Lewis, J.; Kim, E.; Sheng, M.; MacKinnon, R. (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. ISSN 0092-8674. PMID 8674113.
  8. ^ Hopper, Rachel; Lancaster, Barrie; Garthwaite, John (2004-04-01). "On the regulation of NMDA receptors by nitric oxide". The European Journal of Neuroscience. 19 (7): 1675–1682. doi:10.1111/j.1460-9568.2004.03306.x. ISSN 0953-816X. PMID 15078541.
  9. ^ a b Cao, T. T.; Deacon, H. W.; Reczek, D.; Bretscher, A.; von Zastrow, M. (1999-09-16). "A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor". Nature. 401 (6750): 286–290. doi:10.1038/45816. ISSN 0028-0836. PMID 10499588.
  10. ^ Ponting CP (February 1997). "Evidence for PDZ domains in bacteria, yeast, and plants". Protein Sci. 6 (2): 464–468. doi:10.1002/pro.5560060225. PMC 2143646. PMID 9041651.
  11. ^ a b c 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.
  12. ^ 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. doi:10.1016/S0896-6273(00)80663-7.
  13. ^ 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. doi:10.1136/jmedgenet-2011-100590. ISSN 1468-6244. PMID 22510445.
  14. ^ Ranganathan, Rama; Ross, Elliott M (1997-12-01). "PDZ domain proteins: Scaffolds for signaling complexes". Current Biology. 7 (12): R770–R773. doi:10.1016/S0960-9822(06)00401-5.
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Theyellowdart22/sandbox&oldid=923450424"