Sequence and structure‐based characterization of ubiquitination sites in human and yeast proteins using Chou's sample formulation

Abstract

Ubiquitination is an important post‐translational event responsible for half‐life and turnover of proteins inside the cell. Proteins are ubiquitinated by forming an iso‐peptide bond between their lysine residue and C‐terminal glycine residue of ubiquitin leading to rapid degradation of proteins by 26S proteosome complex. Deregulation of ubiquitination is manifested by aberrant expression of E3‐ligase activity or mutation in the surroundings of ubiquitination sites. Many new experimentally validated ubiquitinated lysines have been recently identified that motivated the study of the environments surrounding the ubiquitinated lysines. With the help of known ubiquitinated proteins, here we present a comprehensive study of sequence and spatial environment of ubiquitination sites of human and yeast proteins. To identify position‐specific features, this work distinguishes the spatial environments as proximity and distal regions. Certain amino acids specific to these regions, well differentiate the ubiquitination sites from non‐ubiquitination sites are revealed. Additionally, amino acid signatures that contribute for protein disordered regions and solvent accessibility of amino acids are found to be contributing factors in ubiquitination sites. These results suggest that the ubiquitination site environment of the substrate determines the recognition and unfolding of substrate to facilitate the entry into 26S proteosomal complex. We believe that these findings will help in better prediction of ubiquitination sites using the sequence and spatial information.

Proteome-Wide Analysis of Protein Lysine N-Homocysteinylation in Saccharomyces cerevisiae

“…Proteome-wide mapping of yeast ubiquitination sites and analysis of the protein primary structure identified the amino acids over-represented (A, E, G, K, Q, and R) and under-represented (L, F, H, and W) around ubiquitinated sites in yeast . This is somewhat similar with our finding of A and Q and A and G being over-represented in the proximity of in vivo and in vitro N -Hcy-Lys sites, respectively.…”

“…51 Proteome-wide mapping of yeast ubiquitination sites and analysis of the protein primary structure identified the amino acids over-represented (A, E, G, K, Q, and R) and underrepresented (L, F, H, and W) around ubiquitinated sites in yeast. 52 This is somewhat similar with our finding of A and Q and A and G being over-represented in the proximity of in vivo and in vitro N-Hcy-Lys sites, respectively. Although there are also differences, our other over-represented residues are L, V, and P, while under-represented residues are K, R, S, N, and D. The secondary structure analysis of in vivo N-homocysteinylated sites revealed that there is a tendency of the beta strand to be a preferred structure, while in the case of ubiquitination sites, a tendency for sheet, turn, and coil conformation is observed.…”

“…Although there are also differences, our other over-represented residues are L, V, and P, while under-represented residues are K, R, S, N, and D. The secondary structure analysis of in vivo N-homocysteinylated sites revealed that there is a tendency of the beta strand to be a preferred structure, while in the case of ubiquitination sites, a tendency for sheet, turn, and coil conformation is observed. 52 Our data show that N-homocysteinylation in vivo targets proteins involved in glycolysis/gluconeogenesis, carbon metabolism, methane metabolism, biosynthesis of amino acids, antibiotics, and secondary metabolites, ribosomes, and metabolic pathways, implying that this modification may have a detrimental effect on cell functions. Additionally, by preventing other PTMs, it may interfere with regulation of gene expression and protein turnover.…”

GBDT_KgluSite: An improved computational prediction model for lysine glutarylation sites based on feature fusion and GBDT classifier

“…It has one irregular secondary structure type, the coil region, along with two regular secondary structure states, the -helix (H), and -strand (E) (C). Structural information has been applied to several types of PTM prediction, including succinylation [ 36 ], ubiquitination [ 37 ], and malonylation [ 38 ]. However, as far as we are aware, it has not yet been used for Kglu's prediction.…”