Abstract
Post-translational modification (PTM) of proteins by ubiquitination is an essential cellular regulatory process. Such regulation drives the cell cycle and cell division, signalling and secretory pathways, DNA replication and repair processes and protein quality control and degradation pathways. A huge range of ubiquitin signals can be generated depending on the specificity and catalytic activity of the enzymes required for attachment of ubiquitin to a given target. As a consequence of its importance to eukaryotic life, dysfunction in the ubiquitin system leads to many disease states, including cancers and neurodegeneration. This review takes a retrospective look at our progress in understanding the molecular mechanisms that govern the specificity of ubiquitin conjugation.
Highlights
Ubiquitination is a reversible post-translational modification (PTM) that affects the fate, function or localization of the modified protein
Using a similar setup we examined how the Parkin R0RBR interacts with different Ser65 variants of the ubiquitin-like proteins (Ubls) domain and ubiquitin
Our studies show that achieving specificity within a given pathway can be established by specific interactions between the enzymatic components of the conjugation machinery, as seen in the exclusive FANCL–Ube2T interaction
Summary
Ubiquitination is a reversible post-translational modification (PTM) that affects the fate, function or localization of the modified protein. The attached molecule can support further building of chains from any of the seven lysines present on the surface of ubiquitin or its N-terminus, providing substantial signal diversity. Ubiquitin itself harbours different functional surfaces, for example the Ile44-hydrophobic patch (Leu8/Ile44/His68/Val70), which supports crucial noncovalent interactions during ubiquitination and signal recognition [7]. The repetition of these surfaces results in localized signal amplification. The ubiquitin signals can be edited or erased by deubiquitylating enzymes (DUBs) regulating the nature and duration of the signal [18]. These enzymes cleave the isopeptide bond at the end of a chain (exopeptidase activity) or within the polymer (endopeptidase activity).
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