UbiHub: a data hub for the explorers of ubiquitination pathways.

MOTIVATION: Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. RESULTS: We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. AVAILABILITY AND IMPLEMENTATION: https://ubihub.thesgc.org.

Venus: Elucidating the Impact of Amino Acid Variants on Protein Function Beyond Structure Destabilisation.

Exploring the functional effect of a non-synonymous coding variant at the protein level requires multiple pieces of information to be interpreted appropriately. This is particularly important when embarking on the study of a potentially pathogenic variant linked to a rare or monogenic disease. Whereas accurate protein stability predictions alone are generally informative, other effects, such as disruption of post-translational modifications or weakened ligand binding, may also contribute to the disease phenotype. Furthermore, consideration of nearby variants that are found in the healthy population may strengthen or refute a given mechanistic hypothesis. Whilst there are several bioinformatics tools available that score a genetic variant in terms of deleteriousness, there is no single tool that assembles multiple effects of a variant on the encoded protein, beyond structural stability, and presents them on the structure for inspection. Venus is a web application which, given a protein substitution, rapidly estimates the predicted effect on protein stability of the variant, flags if the variant affects a post-translational modification site, a predicted linear motif or known annotation, and determines the effect on protein stability of variants which affect nearby residues and have been identified in healthy populations. Venus is built upon Michelanglo and the results can be exported to it, allowing them to be annotated and shared with other researchers. Venus is freely accessible at https://venus.cmd.ox.ac.uk and its source code is openly available at https://github.com/CMD-Oxford/Michelanglo-and-Venus.