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. JOSD1 is a cysteine protease and a member of the Machado-Joseph Domain (MJD) enzyme family. Cloning of the human gene was first described by Nomura et al. (1994). The Josephin domain is a conserved cysteine protease domain found in four human deubiquitylating enzymes: ataxin-3, the ataxin-3-like protein (Ataxin-3L), Josephin-1 (JOSD1), and Josephin-2 (JOSD2). Two of the human Josephin proteins, ataxin-3 and ataxin-3L, each contain a single Josephin domain at their N-terminus plus a flexible C-terminal domain of comparable length. JOSD1 and JOSD2, on the other hand, are each composed solely of a single Josephin domain (Weeks et al., 2011). JOSD1 and JOSD2 have been shown to possess DUB activity although details of their substrate specificity are still largely unknown (Tzvetkov and Breuer, 2007).
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Weeks SD, Grasty KC, Hernandez-Cuebas L, Loll PJ (2011) Crystal structure of a Josephin-ubiquitin complex: evolutionary restraints on ataxin-3 deubiquitinating activity. J Biol Chem 286, 4555-4565.