Overview

E3 ubiquitin ligases recognize substrates through their short linear motifs termed degrons. While degron-signaling has been a subject of extensive study, resources for its systematic screening are limited. To bridge this gap, we are developing DEGRONOPEDIA, a web server that searches for degrons and maps them to nearby residues that can undergo ubiquitination (lysine, cysteine, threonine, and serine)2 and disordered regions proximal to them, which may act as protein unfolding seeds, according to the degron tripartite model1. The server provides the evolutionary context of degrons and reports post-translational modifications and mutations within the degron and its flanking regions as these can modulate the degron’s accessibility3,4. Degrons often occur at the amino or carboxyl end of a protein substrate, acting as initiators of the N-/C-degron pathway, respectively5. Therefore, since they may appear following the protease cleavage5, DEGRONOPEDIA simulates sequence nicking based on experimental data and theoretical predictions and screens for emerging degron motifs. We have also implemented machine learning to predict the stability of protein N- and C-termini, facilitating the identification of substrates of the N-/C-degron pathways.

  1. Guharoy, M., Bhowmick, P., Sallam, M. & Tompa, P. Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system. Nat Commun 7, 10239 (2016).
  2. Squair, D. R. & Virdee, S. A new dawn beyond lysine ubiquitination. Nat Chem Biol 18, 802–811 (2022).
  3. Mészáros, B., Kumar, M., Gibson, T. J., Uyar, B. & Dosztányi, Z. Degrons in cancer. Sci. Signal. 10, eaak9982 (2017).
  4. Eldeeb, M. A., Ragheb, M. A., Soliman, M. H. & Fahlman, R. P. Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways. Neurotox Res 40, 298–318 (2022).
  5. Varshavsky, A. N-degron and C-degron pathways of protein degradation. Proc. Natl. Acad. Sci. U.S.A. 116, 358–366 (2019).

License

Our proprietary algorithms, including those identifying potential secondary and tertiary degrons, generate data available under the Creative Commons Attribution (CC BY) license. However, it's important to understand that certain limitations apply, particularly concerning commercial usage. This is due to our incorporation of external software and datasets in our processes, which may have their own licensing restrictions. The data presented at this website is made for scientific purposes. Users cannot use commercially data coming from external software and datasets if according to licensing restrictions they are not allowed to do so. Users are advised to review these conditions carefully before applying our data in commercial projects.

Table. List of external datasets/software used by DEGRONOPEDIA along with their licenses.
Name Description License Free to all users?
Degrons List of all degron motifs from different sources Varies; the license for each degron is reported ✅ / ❌
UniProt Proteomes of selected model organisms CC BY 4.0 ✅
AlphaFold Protein Structure Database Structural models for proteomes of selected model organisms CC BY 4.0 ✅
DSSP Software to calculate secondary structure and relative solvent accesibility (RSA) Boost Software License ✅
IUPred3 Software to predict disorder regions based on the query sequence Other ❌
eggNOG5 Dataset of pre-calculated Multiple Sequence Alignments (MSAs) of orthologs CC BY ✅
iPTMNet Dataset of post-translational modifications CC BY-NC-SA ❌
PhosphoSitePlus Dataset of post-translational modifications CC BY-NC-SA ❌
Plant PTM Viewer Dataset of post-translational modifications Not licensed ✅
PLMD Dataset of post-translational modifications Other ✅
BioGRID Dataset of interactome MIT ✅
IntAct Dataset of interactome CC BY ✅
UbiNet 2.0 Dataset of interactome Other ❌
COSMIC Dataset of mutations in human protein-coding genes Other ❌
MEROPS Dataset of experimental proteolytic sites and enzymes GNU Library General Public License ✅
Pyteomics Software for theoretical predictions of proteolysis Apache-2.0 ✅

Contact

Would you like to share your opinion, suggest a new feature or report a bug? Or maybe you would like to use DEGRONOPEDIA in your research and discuss the possibility of a collaborative project? In any case, please contact Natalia Szulc and Wojciech Pokrzywa.

Reporting new degron motifs

Are you publishing any new degron motifs? We would appreciate if you could drop us a line (see above) so that we can include new degron motifs in the DEGRONOPEDIA.

Acknowledgments

We would like to thank Dr. Natalia Guminska for preparing the DEGRONOPEDIA's logo, see more of her work on her blog.
FeatureViewer was used to visualize degrons in the sequence and ProSeqViewer to visualize degrons in the Multiple Sequence Alignments.
All graphics in the Tutorial were created in BioRender.com.

This research was supported by the National Science Centre, Poland (grant PRELUDIUM number 2021/41/N/NZ1/03473 to Natalia A. Szulc; grant SONATA BIS number 2021/42/E/NZ1/00190 to Wojciech Pokrzywa; grant OPUS number 2020/39/B/NZ2/03127 to Filip Stefaniak; grant MAESTRO number 2017/26/A/NZ1/01083 to Janusz M. Bujnicki). Andrea Cappannini was supported by the ROPES ITN grant from the European Commission [H2020-MSCA-ITN-2020, GA No. 956810, CA16120]. Chiara Maniaci was supported by a BBSRC Discovery Fellowship (BB/T009454/2).

Citing

If you used DEGRONOPEDIA, please cite:

Natalia A Szulc, Filip Stefaniak, Małgorzata Piechota, Anna Soszyńska, Gabriela Piórkowska, Andrea Cappannini, Janusz M Bujnicki, Chiara Maniaci & Wojciech Pokrzywa
DEGRONOPEDIA: a web server for proteome-wide inspection of degrons. Nucleic Acids Research, 2024
doi: 10.1093/nar/gkae238