UbiBrowser 2.0: a comprehensive resource for proteome-wide known and predicted ubiquitin ligase/deubiquitinase–substrate interactions in eukaryotic species

Abstract

As an important post-translational modification, ubiquitination mediates ∼80% of protein degradation in eukaryotes. The degree of protein ubiquitination is tightly determined by the delicate balance between specific ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase-mediated deubiquitination. In 2017, we developed UbiBrowser 1.0, which is an integrated database for predicted human proteome-wide E3–substrate interactions. Here, to meet the urgent requirement of proteome-wide E3/deubiquitinase–substrate interactions (ESIs/DSIs) in multiple organisms, we updated UbiBrowser to version 2.0 (http://ubibrowser.ncpsb.org.cn). Using an improved protocol, we collected 4068/967 known ESIs/DSIs by manual curation, and we predicted about 2.2 million highly confident ESIs/DSIs in 39 organisms, with >210-fold increase in total data volume. In addition, we made several new features in the updated version: (i) it allows exploring proteins’ upstream E3 ligases and deubiquitinases simultaneously; (ii) it has significantly increased species coverage; (iii) it presents a uniform confidence scoring system to rank predicted ESIs/DSIs. To facilitate the usage of UbiBrowser 2.0, we also redesigned the web interface for exploring these known and predicted ESIs/DSIs, and added functions of ‘Browse’, ‘Download’ and ‘Application Programming Interface’. We believe that UbiBrowser 2.0, as a discovery tool, will contribute to the study of protein ubiquitination and the development of drug targets for complex diseases.

Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5‐fluorouracil resistance in gastric cancer

“…In order to explore the underlying mechanism of how OVAAL protects PC from protein degradation, we used UbiBrowser 2.0 ( http://ubibrowser.ncpsb.org.cn ) to predict the potential E3 ligase of PC. 31 UbiBrowser 2.0 predicted that HSC70 was the potential protein that interacted with PC to induce ubiquitin degradation. To validate the prediction, we used the Co‐IP assay followed by mass spectrometry to compare PC binding proteins in control and OVAAL knockdown cells (Figure 6A ).…”

Narrow funnel-like interaction energy distribution is an indicator of specific protein interaction partner.

“…To apply this deep learning method to predict substrates of EULs and kinases, I retrieved EULs and kinases from various species along with information about their substrates from the Ubibrowser2.0 (25) and PhosphoSitePlus (56) databases. Then, I retrieved predicted structures in the AlphaFold database (57) with less than 700 residues and more than 70% prediction confidence in at least half the region.…”

“…Using NumPy's random number generator (77), 106 random, not identified as interacting pairs in literatures and datasets, were generated (Supplementary Data 1). From the E3 ubiquitin ligase-substrate interaction database UbiBrowser (25), 189 E3 ubiquitin ligase-substrate interactions were retrieved. Using NumPy's random number generator (77), 124 random, not identified as interacting pairs in literatures and datasets, were generated (Supplementary Data 1).…”

DEGRONOPEDIA - a web server for proteome-wide inspection of degrons

“…To better understand the specificity of the UPS and its deregulation in disease, degron sequences need to be discovered and matched with their respective degradation pathways. Recently, systematic approaches such as high-throughput experimental techniques, state-of-the-art proteomics technologies, and computational tools have been developed to understand the UPS selectivity (Coyaud et al, 2015; De Cesare et al, 2021;Kats et al, 2018; Koren et al, 2018; Nie et al, 2020; Timms et al, 2019; Wang et al, 2022;Yoshida et al, 2015). Biochemical and structural approaches complement the former to broaden our understanding of molecular mechanisms underpinning substrate selection by dedicated E3 ligases (X.…”