Modification of Proteins by Ubiquitin and Ubiquitin-Like Proteins

Abstract

Following the discovery of protein modification by the small, highly conserved ubiquitin polypeptide, a number of distinct ubiquitin-like proteins (Ubls) have been found to function as protein modifiers as well. These Ubls, which include SUMO, ISG15, Nedd8, and Atg8, function as critical regulators of many cellular processes, including transcription, DNA repair, signal transduction, autophagy, and cell-cycle control. A growing body of data also implicates the dysregulation of Ubl-substrate modification and mutations in the Ubl-conjugation machinery in the etiology and progression of a number of human diseases. The primary aim of this review is to summarize the latest developments in our understanding of the different Ubl-protein modification systems, including the shared and unique features of these related pathways.

The ubiquitin-like modifier FAT10 in cancer development

“…In a second step, ubiquitin is transferred to the active site cysteine of a cognate ubiquitin conjugating enzyme (E2) by a transthiolation reaction. Finally, different classes of ubiquitin ligases (E3s) catalyse the isopeptide linkage of ubiquitin to the -amino-group of an internal lysine residue of a substrate protein (Finley, 2009;Kerscher et al, 2006). Ubiquitin itself contains 7 lysine residues (at positions 6, 11, 27, 29, 33, 48 and 63) which are used to build up chains of different linkage types conveying different outcomes for such modified proteins.…”

“…The Nand C-terminal ubiquitin-like domains are 29% and 36% identical to ubiquitin, respectively, arranged in a tandem array and separated by a short linker (Fan et al, 1996;Groettrup et al, 2008;Theng et al, 2014). In contrast to ubiquitin and other ubiquitin-like modifiers which are expressed as inactive precursors and which need to be activated by proteolytic processing at their C-terminus by specific proteases (Kerscher et al, 2006), FAT10 is already synthesized as a mature protein with a free diglycine motif at its C-terminus and can directly be activated and conjugated to substrate proteins (Raasi et al, 2001). A central function of FAT10 modification is to target proteins for degradation by the proteasome (Hipp et al, 2005;Raasi et al, 2001;Schmidtke et al, 2014).…”

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

“…Protein conjugation with Ub and Ubls involves: (1) their maturation by proteases, (2) activation by an E1 activating enzyme, (3) their transfer to an E2-conjugating enzyme and (4) covalent modification, usually on a lysine residue, on the substrate through the action of E3 ligases. The biological outcome of these modifications is very diverse, from protein destruction to regulation of transcriptional activity, subcellular localization, DNA repair, endocytosis, signal transduction and autophagy (Welchman et al, 2005;Kerscher et al, 2006). It is now evident that Ub and Ubls upon their conjugation on substrates are recognized by a set of proteins.…”

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…Covalent conjugation of SUMO to nuclear factors mainly suppresses their activity and/or ability to synergize with other factors, alters their localization and interaction repertoire or increases their stability (Gill, 2005;Hay, 2005;Kerscher et al, 2006). With the increasing number of sumoylated targets, and the common assumption that the effects of SUMO must be mediated through protein interactions, the identification of a protein motif for noncovalent SUMO binding was awaited.…”