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

Abstract

The ubiquitin-proteasome system is a proteolytic pathway that removes damaged and unwanted proteins. Their selective turnover is initiated by ubiquitin (Ub) attachment, mainly by Ub ligases that recognize substrates through their short linear motifs termed degrons. A degradation-targeting degron comprises a nearby Ub-modified residue and an intrinsically disordered region (IDR) involved in interaction with the proteasome. Degron-signaling has been studied over the last decades, yet there are no resources for systematic screening of degron sites to facilitate studies on their biological significance, such as targeted protein degradation approaches. To bridge this gap, we developed DEGRONOPEDIA, a web server that allows exploration of degron motifs in the proteomes of seven model organisms and maps these data to Lys, Cys, Thr, and Ser residues that can undergo ubiquitination and to IDRs proximal to them, both in sequence and structure. The server also reports the post-translational modifications and pathogenic mutations within the degron and its flanking regions, as these can modulate the degron’s accessibility. Degrons often occur at the amino or carboxyl end of a protein substrate, acting as initiators of the N-/C-degron pathway, respectively. Therefore, since they may appear following the protease cleavage, DEGRONOPEDIA simulate sequence nicking based on experimental data and theoretical predictions and screen for emerging degron motifs. Moreover, we implemented machine learning to predict the stability of the N-/C-termini, facilitating the identification of substrates of the N-/C-degron pathways. We are confident that our tool will stimulate research on degron-signaling providing output information in a ready-to-validate context. DEGRONOPEDIA can be freely accessed at degronopedia.com.

Cardiomyocyte external mechanical unloading activates modifications of α‐actinin differently from sarcomere‐originated unloading

“…At the calmodulin-like domain (CaMD, aa 751-892), S784 phosphorylation increased with F/UF relative to F-UF/UF, K864 ubiquitination increased with Mava/UT and F-UF/UF relative to OM/UT and with F-UF/UF, and T822 phosphorylation increased with OM/UT relative to Mava/UT. Some of these stimulus-responsive modifications are part of predicted degron sites such as K71 in the ABD and S784 in the CaMD [21]. Because the ABD is the region most enriched in PTMs per amino acid, several sites were mapped into structural models of a-actinin-2.…”

“…Muscle energetics are tightly coupled to minimal levels of contractile protein [ 12 ], so that ubiquitination of α-actinin and of cellular lysates may assist in reduction of wasteful crossbridge cycling. Gain in K71 ubiquitination, seen with mechanical unloading, is located within a predicted degron [ 21 ]. Other modified sites, like S784p, K181ac, and T347p, could act as phosphodegron sites to initiate ubiquitination [ 51 ].…”

TENT5-mediated polyadenylation of mRNAs encoding secreted proteins is essential for gametogenesis in mice

“…Interestingly, the unfolded C-terminal region of TENT5B has predicted degron sequences not present in its paralogues (Supplementary Fig. 9) 45 . We thus hypothesize that addition of a GFP-tag at the C-terminus, but not the N-terminus, may inhibit ubiquitination, thereby increasing the stability of TENT5B.…”

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

“…In all cases, we used our recently released tool DEGRONOPEDIA ( Szulc et al, 2022 ) (all presented data in this work comply with the DEGRONOPEDIA’s version from 19.09.2022) to screen for the known degron motifs and post-translational modifications (PTMs), simulate proteolysis, calculate the Gravy hydrophobicity index (GHI) of terminal 15 residues ( Kyte and Doolittle, 1982 ) and report experimental or predicted Protein Stability Index (PSI) values ( Koren et al, 2018 ; Timms et al, 2019 ) for 23 residues at each of the N- and C-termini. Additionally, the DEGRONOPEDIA server provided experimentally validated E3s interacting with profilaggrin based on the BioGRID (Biological General Repository for Interaction Datasets) ( Oughtred et al, 2021 ) and IntAct ( Orchard et al, 2014 ) databases.…”