Abstract
Ubiquitination refers to the conjugation of the ubiquitin protein (a small protein highly conserved among eukaryotes) to itself or to other proteins through differential use of ubiquitin’s seven internal linkage sites or the amino-terminal amino group. By creating different chain lengths, an enormous proteomic diversity may be formed. This creates a signaling system that is central to controlling almost every conceivable protein function, from proteostasis to regulating enzyme function and everything in between. Protein ubiquitination is reversed through the activity of deubiquitinases (DUBs), enzymes that function to deconjugate ubiquitin from itself and protein substrates. DUBs are regulated through several mechanisms, from controlled subcellular localization within cells to developmental and tissue specific expression. Misregulation of DUBs has been implicated in several diseases including cancer and neurodegeneration. Here we present a brief overview of the role of DUBs in neurodegeneration, and as potential therapeutic targets.
Highlights
Ubiquitin is a small (8.6 kDa) protein that is well conserved among eukaryotes
Five of the seven classes of DUBs in human are conserved in yeast: ubiquitin specific protease (USPs), ovarian tumor-like proteases (OTUs), ubiquitin carboxyterminal hydrolases (UCHs), Machado–motif interacting with ubiquitin (MIU)-Containing Novel DUB Family (MINDY), and JAB1/MPN/MOV34 metalloenzymes (JAMM/MPN±) [32]
The mutation may be in a gene that encodes a protein that regulates a DUB. An example of this is Spinocerebellar ataxia type 7 (SCA7) which results from CAG-trinucleotide expansion of the Ataxin 7 (ATXN7) gene, leading to polyglutamine expansion of the ATXN7 protein [65]
Summary
Ubiquitin is a small (8.6 kDa) protein that is well conserved among eukaryotes. For example, Drosophila and human ubiquitin share 100% sequence identity. Substrate specificity is mediated by the action of the E3 directly binding the target protein [3] The result of this is that through E3, ubiquitin is able to form diverse linkages, using different lysine residues or the primary amine at the ubiquitin amino-terminus—all of which can participate in polyubiquitin chain formation [4–13]. Five of the seven classes of DUBs in human are conserved in yeast: ubiquitin specific protease (USPs), ovarian tumor-like proteases (OTUs), ubiquitin carboxyterminal hydrolases (UCHs), Machado–MIU-Containing Novel DUB Family (MINDY), and JAB1/MPN/MOV34 metalloenzymes (JAMM/MPN±) [32]. In the second family of DUB, USPs structure includes the core catalytic domain and extensions that are used for substrate or target recognition [39]. The catalytic domains of these cysteine proteases contain ubiquitin-deconjugating isopeptidases that are required for specific substrate binding and linkage formation. This suggests that UPS dysfunction contributes to the accumulation of neurotoxic proteins in neurodegenerative diseases and possibly disease instigation
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