User:Wintertime2029/sandbox

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References for Research Topic

I am looking to edit the PDZ domain page. Including updating information about new PDZ domain proteins and new discoveries in the function I plan on creating and adding an image of the role of PDZ domains and proteins in the binding of receptors to other cellular components. Specifically I am going to add a section about inhibition of PDZ domains, and clear up the role these sequences have on specific binding.

Four sources I am looking at incorporating into my edit are as follows:

  1. http://www.jbc.org/content/290/10/6120.short[1] - Discusses the role of the PDZ domain in the stabilization inside the cell, not just the membrane.
  2. http://jvi.asm.org/content/89/20/10145.short[2] - Discusses a novel PDZ domain protein not mentioned yet on the page.
  3. http://www.pnas.org/content/112/48/14852.short[3] - Shows a secondary binding site of the PDZ domain to a specific protein
  4. https://elifesciences.org/content/5/e16813[4] - Interactions with synaptic proteins
  5. http://www.jneurosci.org/content/35/7/3073.short[5] - Shows a novel PDZ domain protein and it's role in signaling
  6. http://onlinelibrary.wiley.com/doi/10.1002/ange.201411594/full[6] - Discovery of a PDZ domain inhibitor
  7. http://www.sciencedirect.com/science/article/pii/S1740674912000790- inhibition of PDZ domians
  8. http://www.sciencedirect.com/science/article/pii/S0014579312002566?np=y
  9. [7]
  10. [8]
  11. [9]
  12. [10]

Functions[edit | edit source]

PDZ domains have two main funcions: Localizing cellular elements, and regulating cellular pathways. The first discoverd function of the PDZ domains is to anchor receptor proteins in the membrane by binding to both the protein and cytoskeletal components. PDZ domains also has regulatory functions on different signaling pathways.[11] Any protein may have one or several PDZ domains, which can be identical or unique (see figure to right). This difference in the number of domains allows these proteins to be very versatile in the interactions they have. 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.[12] 

Structural Function

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 

lipid membrane at the synapse. PDZ domains are crucial to 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, 

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.

Regulatory Function

Another interesting role played by PDZ domains are also directly involved in the regulation of different cellular pathways. This mechanism of this regulation widely 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.[12] Some prevalent examples of signaling pathway regulation executed by the PDZ domain include enzyme activity, mecahnosensory signaling, and the sorting pathway of endocytosed receptor proteins.[13][14]

An example of enzyme activity regulation performed by PDZ domains is observed in the human protein tyrosine phosphatase non-receptor type 4 (PTPN4). 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 domian of this phosphatase results in a loss of enzyme activity. The loss of functioning PTPN4 results in oncogenic activity.[13]

PDZ domains also have a regulatory roll in mechanosensory signaling in proprioceptors and vestibular and auditory hair cells. The protein Whirlin(WHRN) contains three PDZ domains. Two of these domains located near the N-terminus bind to receptor proteins and The protein WHRN localizes in post-synaptic nerves of hair cells that transform mechanical movement into action potentials that the body can interpret. When the PDZ domain of Whirlin is inhibited, signaling pathways of the neurons in hair cells and propioceptors 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 it's PDZ domain in the cell.[14]

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.[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 domains are being studied further to better understand the role they play in different signaling pathways.

Regulation of PDZ Domain Activity

PDZ domain function can be both inhibited and activated by various mechanism. Three of the most prevalent include allosteric interactions, posttraslational modifications, and auto-inhibition.

Allosteric Interactions

Posttranslational modifications

Auto-inhibition

There are several known inhibitors of PDZ domains. One study showed that peptidyl inhibitors, kinase inhibitors, and CFTR inhibitors all disrupt normal PDZ domain activity.[15] These inhibitors impact different functions of the PDZ domains. The CFTR inhibitors lower binding of the PDZ proteins with the PDZ binding site, which slows down or stops further signaling.[15]

Human PDZ Domains

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;

WHRN
;

  1. ISSN 0021-9258.{{cite journal}}: CS1 maint: unflagged free DOI (link
    )
  2. ISSN 0022-538X
    .
  3. ISSN 0027-8424
    .
  4. ISSN 2050-084X.{{cite journal}}: CS1 maint: unflagged free DOI (link
    )
  5. ISSN 0270-6474
    .
  6. ISSN 1521-3757
    .
  7. PMID 23395182
    .
  8. PMID 17317137
    .
  9. PMID 15821164
    .
  10. PMID 23395182
    .
  11. ^
    PMID 11591811
    .
  12. doi:10.1016/S0092-8674(00)81307-0
    .
  13. ^
    ISSN 1742-4658
    .
  14. ^
    PMID 25698744
    .
  15. ^
    ISSN 1521-3757
    .
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