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UbiNet is a web-based system that provides a comprehensive collection of available ubiquitinated substrate proteins, ligating enzyme E3, E3-substrate specificities and a systematic framework for the analysis of E3 ligase regulatory networks in protein ubiquitination, focusing on Human organism. Currently, UbiNet contains 499 E3s and 14692 ubiquintinated substrate proteins in Human, and 10437 E3-substrate specific relations between 438 E3s and 2839 ubiquitinated substrate proteins. In addition, 2143 records of E3-associated functional categories (including pathway, cellular process, molecular function, cellular localization, protein complex, protein family, and disease) were collected serving for the analysis. The UbiNet system, as shown in Figure 1, contains 4 major parts, including: Networks analysis, E3 Ligases, E3-Associated Functional, and Ubi-Prediction. Besides, the UbiNet system provided some additional other functions (including: Statistics, Download, Help, and Contact) to support users easily in exploiting the UbiNet system.

Figure 1. Homepage of the UbiNet system

 

The details of functionalities are described as follows:

1. Network Analysis. This function was provided to serve for the investigation of regulatory networks in protein ubiquitination. To reconstruct the networks, users need to input a list of genes (containing E3 ligases, ubiquitinated substrate proteins, or interacting proteins). If the query list contains only E3s, our system will visualize networks of these E3s with all possible ubiquitinated substrate proteins. Otherwise, our system will show networks between E3s ligases, ubiqtuinated substrate proteins, and interacting protein in the given list. Figure 2 (default case) presents the E3-substrate regulatory network drawn for the query list of 20 proteins: WWP1; SMURF2; MDM2; SMAD5; CPSF6; ATN1; KLF5; NUMB; ARRB2; JUN; EEF1G; ACOX3; SKIL; GNL3; TAF1; NFE2; TP73; SOCS6; AKAP5; FOXO3; ZNF638; DAB2; VHL; MOB4; HIF1A.

Figure 2. The E3-substrate regulatory network constructed for the default case from function Network Analysis

In addition, our system will check for all interacting proteins (non-Ubi-substrate proteins; non-E3 ligases) and provide the prediction function for these proteins. To see this function, users should follow the two steps, as shown in Figure 3: Step 1. Select one of the interacting proteins; Step 2. Go to the result-page if the query protein is predicted as Ubiquitinated protein. After a while of waiting, the result page will be displayed to show in detail the prediction result for the query protein, as shown in Figure 4.

Figure 3. The UbiSite prediction provided to predict for interacting protein

Figure 4. The results of UbiSite-prediction when predicted for interacting protein {gene: FOXO3; ID: FOXO3_HUMAN}

2. E3 Ligases. This function was provided as a database of E3 ligases. All the relative information was listed as shown in Figure 5, including supporting E3s’ information. Also, the number of Ubi-substrate proteins was calculated and browsed serving for users’ interests. To investigate the information related to each E3 ligase, users just only click on link corresponding to the rows representing for this E3 ligase. For example, if users want to investigate information of all substrate proteins which are potentially recognized by the E3 ligase, they just click on number-link of “No. of protein potentially recognized by E3” column that is corresponding to the row of the E3. Consequently, the results will be displayed in a new form being opened thereafter. Figure 6 shows results of all substrate protein which are potentially regulated by the E3 ligase having ID = ARNT_HUMAN. Similarly, users can directly construct the E3-substrate regulatory networks of this E3 ligase and all possible substrate proteins by clicking on the corresponding Construct-link of the “Networks”. A new form will be opened containing the resulting networks. Figure 7 demonstrated results of interactional regulatory networks regulated by the E3 ligase having ID=ARNT_HUMAN.

Figure 5. Database of E3 Ligases (Function of E3 Ligases)

 

Figure 6. List of all substrate proteins which are recognized by E3{id=ARNT_HUMAN}

 

Figure 7. The E3-substrate regulatory network constructed based on E3{id=ARNT_HUMAN} recognition

 

3. E3-Associated Functional. This page shows all E3 ligases along with its associated functional category (including: pathway, disease, cellular protein, cellular localization, molecular function, protein complex, and protein family), as shown in Figure 8. In addition, this page provides function to construct and view the interacting network between E3 ligase and substrate proteins.

Figure 8. The web-page of function E3-Associated Functional

4. Ubi-Prediction. In addition to the investigation of E3-substrate regulatory networks in protein ubiquitination, we provided UbiSite-prediction function as a ubiquitination sites prediction tool for all 7600 unique interacting proteins (proteins were not verified as E3 ligases or ubiquitinated substrate proteins) in our current database. Applying Support Vector Machine, and our previous work of UbiSite, we predicted for all these 7600 unique interacting proteins and using SVM-score to conclude whether a site is ubiquitination site. Also the corresponding substrate motif is provided to users for their further investigations. The results, as shown in Figure 9, including: Protein ID; Ubiquitination site/position; the corresponding fragment; SVM-score; and the corresponding substrate motif.

Figure 9. The web-page of functionUbi-Prediction

5. Statistics. All the data served for this study were summarized in this function.

6. Download. This page will direct users go to the page, where they can freely download our data for their further analysis.

7. Help. This function will help provide more understanding about our system and the its functions, so that users can exploit our systems and its functions in such a effective and effecient ways.

8. Contact. If have any problems or any questions, users can contact with us via this function by sending email.