InterPro domain: IPR044098

This domain is known as the MPN domain [ 1 ], PAD-1-like domain [ 2 ], JABP1 domain [ 3 ] or JAMM domain [ 4 ]. Proteins with this domain include proteasome regulatory subunits, eukaryotic initiation factor 3 (eIF3) subunits and regulators of transcription factors. They are metalloenzymes that function as the ubiquitin isopeptidase/deubiquitinase in the ubiquitin-based signaling and protein turnover pathways in eukaryotes [ 5 ]. Versions of the domain in prokaryotic cognates of the ubiquitin-modification pathway are predicted to have a similar role [ 5 ].

This entry represents the MPN domain found in human STAMBP (also known as AMSH) and STALP (also known as AMSH-LP) proteins. They are Zn-dependent deubiquitinating enzymes (DUBs) that regulate receptor trafficking by specifically cleaving Lys 63-linked polyubiquitin chains from internalised receptors [ 6 ]. Mutations in the STAMBP gene cause microcephaly-capillary malformation syndrome [ 7 ].

1. The PCI domain: a common theme in three multiprotein complexes. Trends Biochem. Sci. 23, 204-5
2. Eukaryotic signalling domain homologues in archaea and bacteria. Ancient ancestry and horizontal gene transfer. J. Mol. Biol. 289, 729-45
3. A global census of fission yeast deubiquitinating enzyme localization and interaction networks reveals distinct compartmentalization profiles and overlapping functions in endocytosis and polarity. PLoS Biol. 8, 611-5
4. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 556-62
5. The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like beta-grasp domains. Genome Biol. 7, R60
6. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455, 358-62
7. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat. Genet. 45