Abstract
Ubiquitination of proteins is a sophisticated post-translational modification implicated in the regulation of an ever-growing abundance of cellular processes. Recent insights into different layers of complexity have shaped the concept of the ubiquitin code. Key players in determining this code are the number of ubiquitin moieties attached to a substrate, the architecture of polyubiquitin chains, and post-translational modifications of ubiquitin itself. Ubiquitination can induce conformational changes of substrates and alter their interactive profile, resulting in the formation of signaling complexes. Here we focus on a distinct type of ubiquitination that is characterized by an inter-ubiquitin linkage through the N-terminal methionine, called M1-linked or linear ubiquitination. Formation, recognition, and disassembly of linear ubiquitin chains are highly specific processes that are implicated in immune signaling, cell death regulation and protein quality control. Consistent with their role in influencing signaling events, linear ubiquitin chains are formed in a transient and spatially regulated manner, making their detection and quantification challenging.
Highlights
Ubiquitination is a reversible post-translational modification that can affect the function, the fate, and the subcellular localization of the modified substrates, thereby regulating fundamental cellular processes (Akutsu et al, 2016; Swatek and Komander, 2016; Yau and Rape, 2016)
E3 ubiquitin ligases fall into three categories: really interesting new gene (RING)/U-box ligases, RBR (RING-between-RING) ligases, and HECT ligases
Ubiquitination is the most versatile post-translational modification based on variabilities in the number of ubiquitin moieties attached to a substrate, the mode of inter-ubiquitin linkage, and the formation of heterotypic ubiquitin chains
Summary
Ubiquitination is a reversible post-translational modification that can affect the function, the fate, and the subcellular localization of the modified substrates, thereby regulating fundamental cellular processes (Akutsu et al, 2016; Swatek and Komander, 2016; Yau and Rape, 2016). HECT ligases directly bind ubiquitin by forming a thioester intermediate via a catalytic cysteine residue From this thioester ubiquitin is passed on to a lysine residue of the substrate, generating an isopeptide bond. Ubiquitin is transferred from the E2 to a catalytic cysteine in the RING2 domain forming a transient thioester, to HECT ligases. This ubiquitin moiety is attached to the target protein. Ubiquitination is the most versatile post-translational modification based on variabilities in the number of ubiquitin moieties attached to a substrate, the mode of inter-ubiquitin linkage, and the formation of heterotypic (mixed or branched) ubiquitin chains. Each linkage-type has a distinct three-dimensional topology allowing interactions with linkage-specific effector proteins, resulting in specific biological outcomes (Figure 3)
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