Death Domain database

Death Domain Database
Figure 1. Overview of the DD database web interfaces, with a reconstituted illustration. (A) Main page (B) Search result (C) PPI in detail (D) PPIs at a glance (E) 3D structure information (F) Interaction map.
Content
Description protein-protein interaction database for the Death Domain superfamily.
Contact
Authors Dongseop Kwon
Primary citation Kwon & al. (2012)[1]
Release date 2011
Access
Website http://www.deathdomain.org

The Death Domain database is a secondary database of protein-protein interactions (PPI) of the death domain superfamily.[1] Members of this superfamily are key players in apoptosis, inflammation, necrosis, and immune cell signaling pathways. Negative death domain superfamily-mediated signaling events result in various human diseases which include, cancers, neurodegenerative diseases, and immunological disorders. Creating death domain databases are of particular interest to researchers in the biomedical field as it enables a further understanding of the molecular mechanisms involved in death domain interactions while also providing easy access to tools such as an interaction map that illustrates the protein-protein interaction network and information. There is currently only one database that exclusively looks at death domains but there are other databases and resources that have information on this superfamily.[1] According to PubMed,[2] this database has been cited by seven peer-reviewed articles to date because of its' extensive and specific information on the death domains and their PPI summaries.

The Death Domain Superfamily

The evolutionarily conserved Death Domain superfamily is defined by a death fold motif and is formed by interacting with other protein domains.[3] This superfamily is considered one of the largest and most studied protein-protein interaction (PPI) network. The domains consist of six-seven tightly coiled alpha-helices arranged in a “Greek-key fold".[1][3]

There are four types of death domain subfamilies: death effector domain (DED),[4] caspase recruitment domain (CARD),[5] pyrin domain (PYD), and death domain (DD).[1][6] These subfamily domains are grouped together because of similarity in their sequence and structure.[7] However, while similar, each domain has its own defining structural feature: a RxDL-motif in the DEDs, an interrupted, first helix in the CARDs, a smaller (or sometimes ambiguous) third helix in PYDs, and a more exposed, flexible third helix in the DDs.[1] Members of this subfamily only form homotypic bonds with the same type of subfamily domain. For example, DED will only bind with DED, CARD-CARD, PYD-PYD and DD-DD. These homotypic interactions are with only two members of the same domain (or on rare occasions with more) and there has been no evidence to suggest that these domains have heterotypic interactions with one another.[3]

Death Domain Subfamilies

Death Effector Domain (DED)

DED domains are highly conserved in the Chordata phylum and can also be found in smaller percentages in the Echinodermata phylum and viruses.[8] DED-containing proteins are associated with apoptosis regulation with caspase protein interaction and have been notably documented in mammals.[3][9] DED domains have been known to interact with other domains and include: nuclear localization sequences (in DEDD), transmembrane domains (in Bap31 and Bar), nucleotide-binding domains (in Dap3), SAM domains (in Bar), coiled-coil domains (in Hip and Hippi), and E2-binding RING domains (in Bar).[10]

Caspase Recruitment Domain (CARD)

CARD domains are primarily found in chordates, with many being from the animal kingdom, and are found in smaller percentages in Nematoda and Echinodermata phylums.[11] Protein modules containing the CARD domain are associated with apoptosis, through the regulation of caspases that they are interacting with, as well in inflammation processes through its participation in NF-kappaB signaling pathways.[12]

Pyrin Domain (PYD)

The PYD domain, also known as the Domain in Apoptosis and INterferon response (DAPIN) domain, is typically found in vertebrates and viral proteins and are involved in apoptosis, cancer, and inflammation.[13] The functions of this group are the least understood among the 4 members of the death domain superfamily.[3]

Death Domain (DD)

This domain is predominantly found in the animal kingdom, especially among mammals, who have many different types of PPI’s containing death domains.[7] According to SMART’s non-redundant database, mammals have about 61% of known DD-domains.[14] DD-containing proteins are associated with apoptosis and inflammation, similar to the CARD domain. It has also been linked with innate immunity.[15] DD’s can also be found with other types of domains including Ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.[7]

Overview

Deathdomain.org was initially created by Kwon et al. (2012) to stimulate further research into the death domain superfamily mediated signaling pathway. Their database is manually curated and focuses on providing detailed information on the death domain superfamily and its protein-protein interactions. Kwon and his team started by researching, compiling and curating 295 published peer-reviewed studies that focused on PPI modules and their associated death domains. The database now provides users with information from 311 peer-reviewed studies, a slight increase from the original publication.[1]

This database provides:

Constructing the Database

PubMed database[2] was the primary source used for data collection in the DeathDomain.org database. The authors for the site started by finding synonyms for the 99 death domain superfamily proteins from UniProtKB[16] and Entrez Gene.[17] Along with the protein name, synonyms were used to search for articles in the PudMed database for death domain proteins that were involved in physical binding to other proteins. Further searches were done on DIP,[18] IntAct,[19] MINT[20] and STRING [21] databases to ensure that all relevant articles were included in the study. The authors were able to find and manually curate 295 peer-reviewed articles that discussed 175 PPI pairs among 99 DD superfamily proteins. These numbers have increased since the original publication to 311 peer-reviewed papers discussing 181 PPI pairs among 99 DD superfamily proteins.[1]

To curate data in the literature, the authors chose to focus on the analytical methods, experimental results, resources, and nomenclature. If there was insufficient data in the papers, users will see "Not specified" in these sections.[1]

Layout

The death domain database layout is very user-friendly and offers users with five tabs on the upper-left corner linking them to various tools and information sources. They are: "Home" tab- an overview of the death domain database and content (Fig. 1A), the "Statistics" tab- tabulated statistics regarding the death domain superfamily mediated PPIs, the "Interaction map" tab- an interactive visualization tool for the death domain superfamily mediated PPIs (Fig. 1F), the "Tutorial" tab- detailed instructions on how to navigate and use the database and "About us" tab-information about the Deathdomain.org staff and how to cite the database.[22]

On the far left of the website, users can also take advantage of the 6 tabs linking them to an overview of the death domain superfamily, comprehensive information on the four members that make up the subfamily, and a link to the publication. The subfamily tabs also have subtabs that provide details about their associated PPIs.

The Death Domain logo on the top left also navigates users to back to the home page.

Features

DD Superfamily and PPI Summaries

This feature can be accessed by picking a death domain of interest and using the subtab to pick a protein containing this domain. It will take the user to a wealth of information that can be seen in great detail (“In detail” tab) or in lesser detail (“At a glance” tab) on top (Fig. 1D and 1C, respectively). The data is further broken down into three categories: interaction, characterization, and functional role. These categories were chosen because they were used in similar studies.[23] In most cases, for each PPI, users can learn more about them by clicking the PubMed ID, giving details including the title, abstract, authors, interactions mentioned in the article, and a link to the publication.[24]

Other subheading tabs give access to protein information including the proteins full name, alternative names, function, and death domain subfamily and boundary region. The latter conveniently allows users to obtain the amino acid sequences and domain boundaries from UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases in either embl, genbank or fasta format.[16] By clicking the external database link, users can get this information for the domain-containing protein found in other species. They can also access more information on similar databases (Uniprot, DIP, STRING, KEGG, IntAct, and MINT) by clicking the appropriate identifier number. The last two tabs will provide users with downloadable 3-D structure images under the "3-D structure" tab and the natural mutations and related diseases they are involved in under the "Disease" tab (Fig. 1E).[24]

DeathDomain Database Search

The search engine feature on Deathdomain.org allows users to make simple searches by inputting keywords into the search box located in the upper right corner (Fig. 1B). The search feature will scan the whole website for the keyword and will layout the data retrieved into two categories: Death Domain and References. If a keyword is searched that is part of a protein name or a UniprotKB ID, these results will be shown and detailed information on each PPI can be accessed by clicking on the protein name. This feature is also the same for keywords found in publications including the title, authors, source, abstract, or PMID where more information is made available by clicking the article name. Another feature of the search box is that it will give you a search query example on the results page outlining how to use the search box. Like many search engines, if more than one keyword is entered the information retrieved will contain both keywords.[25]

Statistics

The statistics page consists of a list of publications (separated by year of publication) used in the database and can be accessed via a hyperlink. The page also presents tabulated summaries of the number of PPIs per domain and are also hyperlinked to their PPI summary page. Another tabulated feature is a comparison of the DD superfamily mediated PPI pairs found on the Death Domain database to other PPI databases. This page illustrates to users that their database has more PPI pairs than Deathbase.org and the same number as IntAct and Mint.[26]

Interaction Map

This user-friendly interactive tool allows users to easily visualize the relationships of the death domain subfamilies and their associated PPI's. The map is made up of a web of nodes where nodes represent a DD-containing protein that connects to other nodes illustrating PPI's for each domain subfamily member. More information can be accessed for each PPI by double-clicking on the nodes. A control panel on the left side of the map also allows users to emphasize what death domain they would like to see and by PPI category (in-vivo or in-vitro validation).[27]

Tutorial

The tutorial section is a useful feature that gives users detailed instructions on how to use and navigate through the website. The sections covered include the home page, the death domain subfamily and PPI summaries pages, keyword search, and the interaction map. The explanations are aided by a screenshot image from the website page.[28]

Other Resources

Database Name Type of Database Features Organisms in Database
Deathbase[29] Database of proteins involved in cell death -Data on function, structure, and evolution of proteins involved in apoptosis/ other forms of cell death

-Manually curated data

-Easy searches based on species, protein, pathway, family, and domain names

 Human

Mouse

Zebrafish

Fly

Worm

IntAct Molecular interaction database -Open source database system and includes analysis tools for molecular interaction data

-Manually curated data (from EMBL-EBI)

-Comprehensive search options: Gene, Protein, RNA, Chemical name, UniProtKB, ChEBI AC, UniProtKB ID, RNACentral ID, PMID, and IMEx ID

 Cellular organisms

Viruses

Many others

MINT[20] Molecular interaction database -Experimentally verified protein-protein interaction data

-Manually curated data

-Easy search options: species, protein, gene name, UniProt Protein Accession Number, and PubMed id/D.O.I

 Human

Yeast

Fruit Fly

Worm

STRING[21] Protein-protein interaction network database -Data on known and predicted protein-protein interactions: direct (physical) and indirect (functional) association

-Manually curated data

-Easy search options: Species, protein name, and Identifier

 2031 total organisms
DIP[18] Protein-protein interaction network database -Data on experimentally determined interactions between proteins

-Manually curated data

Easy search options: protein, sequence, motif, article, IMEx, and pathBLAST

 Human

Yeast

Fruit Fly

Many others

References

  1. 1 2 3 4 5 6 7 8 9 Kwon, Dongseop; Yoon Jong Hwan; Shin Soo-Yong; Jang Tae-Ho; Kim Hong-Gee; So Insuk; Jeon Ju-Hong; Park Hyun Ho (Jan 2012). "A comprehensive manually curated protein-protein interaction database for the Death Domain superfamily". Nucleic Acids Research. 40 (D1): D331–D336. doi:10.1093/nar/gkr1149. PMC 3245059Freely accessible. PMID 22135292.
  2. 1 2 Sayers, EW; Barrett, T; Benson, DA; Bolton, E; Bryant, SH; Canese, K; Chetvernin, V; Church, DM; Dicuccio, M; Federhen, S; et al. (2011). "Database resources of the National Center for Biotechnology Information". Nucleic Acids Res. 38: D38–D51. doi:10.1093/nar/gkq1172. PMID 21097890.
  3. 1 2 3 4 5 Lahm, A; Paradiso, A; Green, D. R.; Melino, G (2003). "Death fold domain interaction in apoptosis". Cell Death and Differentiation. 1 (1): 10–12. doi:10.1038/sj.cdd.4401203. ISSN 1350-9047. PMID 12655289.
  4. ↑ Chinnaiyan, AM; O'Rourke, K; Tewari, M; Dixit, VM (1995). "FADD, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis". Cell. 81 (4): 505–512. doi:10.1016/0092-8674(95)90071-3.
  5. ↑ Hofmann, K; Bucher, P; Tschopp, J (1997). "The CARD domain: A new apoptotic signalling motif". Trends in Biochemical Sciences. 22 (5): 155–156. doi:10.1016/S0968-0004(97)01043-8. ISSN 0968-0004.
  6. ↑ Tartaglia, LA; Ayres, TM; Wong, GHW; Goeddel, DV (1993), "A novel domain within the 55 kd TNF receptor signals cell death", Cell, 74 (5): 845–53, doi:10.1016/0092-8674(93)90464-2
  7. 1 2 3 Death domain (IPR000488), retrieved 3 November 2016
  8. ↑ Thomas, L; Henson, A; Reed, JC; Salsbury, FR; Thorburn, A (2004). "Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD". The Journal of Biological Chemistry. 279 (31): 32780–5. doi:10.1074/jbc.M401680200. PMID 15173180.
  9. ↑ DED: Death effector domain, retrieved 3 November 2016
  10. ↑ Reed, JC; Doctor, KS; Godsik, A (2004). "The domains of apoptosis: A genomics perspective". Science's STKE. 2004 (239): re9. doi:10.1126/stke.2392004re9.
  11. ↑ CARD: Caspase recruitment domain, retrieved 3 November 2016
  12. ↑ Bouchier-Hayes, L; Martin, SJ (2002). "CARD games in apoptosis and immunity". EMBO Reports. 3 (7): 616–621. doi:10.1093/embo-reports/kvf139. PMC 1084193Freely accessible. PMID 12101092.
  13. ↑ Staub, E.; Dahl, E; Rosenthal, A (2001). "The DAPIN family: A novel domain links apoptotic and interferon response proteins". Trends in Biochemical Sciences. 26 (2): 83–85. doi:10.1016/S0968-0004(00)01717-5.
  14. ↑ DEATH: DEATH domain, found in proteins involved in cell death (apoptosis)., retrieved 3 November 2016
  15. ↑ O'Neill, LA; Dunne, A; Edjeback, M; Gray, P; Jefferies, C; Wietek, C (2003), "Mal and MyD88: Adapter proteins involved in signal transduction by toll-like receptors", Journal of Endotoxin Research, 9 (1): 55–59, ISSN 0968-0519
  16. 1 2 The UniProt Consortium (2010). "The Universal Protein Resource (UniProt) in 2010". Nucleic Acids Res. 38: D142–D148. doi:10.1093/nar/gkp846. PMC 2808944Freely accessible. PMID 19843607.
  17. ↑ Maglott, D; Ostell, J; Pruitt, KD; Tatusova, T (2011). "Entrez Gene: gene-centered information at NCBI". Nucleic Acids Res. 39: D52–D57. doi:10.1093/nar/gkh086. PMC 3013746Freely accessible.
  18. 1 2 Salwinski, L; Miller, CL; Smith, AJ; Pettit, FK; Bowie, JU; Eisenberg, D (2004). "The Database of Interacting Proteins: 2004 update". Nucleic Acids Res. 32: D449–D451. doi:10.1093/nar/gkq1237. PMC 308820Freely accessible.
  19. ↑ Aranda, B; Achuthan, P; Alam-Faruque, Y; Armean, I; Bridge, A; Derow, C; Feuermann, M; Ghanbarian, AT; Kerrien, S; Khadake, J; et al. (2010). "The IntAct molecular interaction database in 2010". Nucleic Acids Res. 38: D525–D531. doi:10.1093/nar/gkp878. PMC 2808934Freely accessible. PMID 19850723.
  20. 1 2 Ceol, A; Chatr Aryamontri, A; Licata, L; Peluso, D; Briquanti, L; Perfetto, L; Castagnoli, L; Cesareni, G (2010). "MINT, the molecular interaction database: 2009 update". Nucleic Acids Res. 38: D532–D539. doi:10.1093/nar/gkp983. PMC 2808973Freely accessible.
  21. 1 2 Szklarcyk, D; Francheschini, A; Kuhn, M; Simonovic, M; Roth, A; Minquez, P; Doerks, T; Stark, M; Muller, J; Bork, P; et al. (2011). "The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored". Nucleic Acids Res. 39: D561–D568. doi:10.1093/nar/gkq973. PMC 3013807Freely accessible.
  22. ↑ "Death Domain database: A manually curated database of protein-protein interactions for Death Domain Superfamily". Deathdomain. Retrieved 3 Nov 2016.
  23. ↑ Xenarios, I; Eisenberg, D (2001). "Protein interaction databases" (PDF). Curr. Opin. Biotechnol. 12: 334–339.
  24. 1 2 "Detailed Information on The Death Domain Superfamily and PPIs". Deathdomain. Retrieved 3 November 2016.
  25. ↑ "Death Domain Database Search". Deathdomain. Retrieved 3 November 2016.
  26. ↑ "Statistics". Deathdomain. Retrieved 3 November 2016.
  27. ↑ "Interaction Map". Deathdomain. Retrieved 3 November 2016.
  28. ↑ "Tutorial". Deathdomain. Retrieved 3 November 2016.
  29. ↑ "Deathbase.org". Deathbase. Retrieved 1 December 2016.

External links

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