Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al., 2009). The deubiquitylating - or deubiquitinating - enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin dependent signalling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB; cysteine proteases and metalloproteases. Ataxin-3 is a cysteine protease and is a member of the Machado-Joseph Domain (MJD) enzyme family. Cloning of the human gene was first described by Kawaguchi et al. (1994). Machado–Joseph disease (MJD), the most common form of spinocerebellar ataxia worldwide, is a progressive and ultimately fatal neurodegenerative disorder caused by polyQ expansion in ataxin-3, a conserved and ubiquitous protein known to bind polyubiquitin chains and to function as a deubiquitylating enzyme. Ataxin-3 has been linked to protein homeostasis maintenance, transcription, cytoskeleton regulation and myogenesis (Matos et al., 2011). Ataxin-3 is an unusual DUB whose properties favour functional interactions with E3s such as Parkin and CHIP (Durcan et al., 2012; Scaglione et al., 2011). Ataxin-3 contains an amino-terminal protease domain followed by three Ubiquitin Interacting Motifs (UIMs) that bind longer ubiquitin chains. Ataxin-3 also trims longer chains, displaying little activity against chains of four or fewer ubiquitins (Scaglione et al., 2011). The full-length protein has been shown to preferentially cleave Lys-63-linked and mixed-linkage ubiquitin chains. This specificity is imparted by UIMs found in the enzyme C-terminal region, as the isolated Josephin domain cleaves both Lys-48 and Lys-63-linked chains with equal efficiency. Ataxin-3 can also cleave adducts at the C terminus of NEDD8, a protein that is closely related to ubiquitin in both structure and sequence (Weeks et al., 2011).
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