Abstract
Ubiquitin modification (ubiquitination) of target proteins can vary with respect to chain lengths, linkage type, and chain forms, such as homologous, mixed, and branched ubiquitin chains. Thus, ubiquitination can generate multiple unique surfaces on a target protein substrate. Ubiquitin-binding domains (UBDs) recognize ubiquitinated substrates, by specifically binding to these unique surfaces, modulate the formation of cellular signaling complexes and regulate downstream signaling cascades. Among the eight different homotypic chain types, Met1-linked (also termed linear) chains are the only chains in which linkage occurs on a non-Lys residue of ubiquitin. Linear ubiquitin chains have been implicated in immune responses, cell death and autophagy, and several UBDs - specific for linear ubiquitin chains - have been identified. In this review, we describe the main principles of ubiquitin recognition by UBDs, focusing on linear ubiquitin chains and their roles in biology.
Highlights
Ubiquitin, an 8.5 kDa protein conserved from yeast to human, is utilized to post-translationally modify substrate proteins [1,2]
OTU DUB with linear linkage specificity” (OTULIN) negatively regulates various signaling cascades in which linear ubiquitination plays a role, such as immune signaling cascades and the cell death pathway mediated by the “tumor necrosis factor (TNF) Receptor” (TNFR) or “Nucleotide-binding Oligomerization Domain-containing protein 2” (NOD2) (Fig. 3A)
The first linear ubiquitin chain-specific ubiquitin-binding domain (UBD) was discovered in NF-jB essential modulator” (NEMO) and shown to regulate the inflammatory NF-jB signaling cascade [19]
Summary
An 8.5 kDa protein conserved from yeast to human, is utilized to post-translationally modify substrate proteins [1,2]. Recent studies have shown that ubiquitin can be phosphorylated, acetylated, sumoylated, and neddylated These modifications of ubiquitin potentially alter the UBD-binding surface or chain formation [20,21,22], it is tempting to speculate that there are distinct UBDs recognizing chains with modified ubiquitins as a monomer or as a chain (Fig. 2C,D). NEMO plays an important role as part of the “IjB Kinase” (IKK) complex in the “Nuclear Factor-KappaB” (NF-jB) activation signaling cascade, both as a linear ubiquitination substrate and linear ubiquitin chain binding protein (Fig. 3A). A structural study of OPTINEURIN-UBAN in complex with linear tetraubiquitins revealed a binding mode similar to that of linear ubiquitin with NEMO and ABIN-2 [23] In this crystal structure, two tetraubiquitin chains within neighboring asymmetric units interact with opposing faces of an UBAN dimer, with two ubiquitins from each chain interacting with one face of a UBAN dimer (Fig. 5D). OPTINEURIN is a negative regulator of the NF-jB signaling cascade (Fig. 3A)
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