The Josephin domain is an eukaryotic protein module of about 180 residues, which occurs in stand-alone form in Josephin-like proteins, and as an amino- terminal domain associated with two or three copies of the ubiquitin- interacting motif (UIM) in ataxin 3-like proteins. Josephin domain-containing proteins function as de-ubiquitination enzymes [ (PUBMED:17696782) ]. Although it has originally been proposed that the Josephin domain could be an all-alpha helical domain distantly related to ENTH and VHS domains involved in membrane trafficking and regulatory adaptor function [ (PUBMED:12486728) ], it is now believed that it is a mainly alpha helical cysteine-protease domain predicted to be active against ubiquitin chains or related substrates [ (PUBMED:12944423) (PUBMED:14559776) ].

The Josephin domain contains two conserved histidines and one cysteine that is required for the ubiquitin protease activity [ (PUBMED:12944423) (PUBMED:14559776) ] and two ubiquitin-binding sites [ (PUBMED:19382171) ].

Some proteins known to contain a Josephin domain are:

• Animal Machado-Joseph disease protein 1 (Ataxin 3). It interacts with key regulators (CBP, p300 and PCAF) of transcription and represses transcription.
• Plant Machado-Joseph disease-like protein (MJD1a-like) (Ataxin 3 homologue).
• Mammalian Josephin 1 and 2.
• Drosophila melanogaster Josephin-like protein.
• Arabidopsis thaliana Josephin-like protein.