Mpr1p, Pad1p N-terminal (MPN) domains; MPN (also known as Mov34, PAD-1, JAMM, JAB, MPN+) domains are found in the N-terminal termini of proteins with a variety of functions; they are components of the proteasome regulatory subunits, the signalosome (CSN), eukaryotic translation initiation factor 3 (eIF3) complexes, and regulators of transcription factors. These domains are isopeptidases that release ubiquitin from ubiquitinated proteins (thus having deubiquitinating (DUB) activity) that are tagged for degradation. Catalytically active MPN domains contain a metalloprotease signature known as the JAB1/MPN/Mov34 metalloenzyme (JAMM) motif. For example, Rpn11 (also known as POH1 or PSMD14), a subunit of the 19S proteasome lid is involved in the ATP-dependent degradation of ubiquitinated proteins, contains the conserved JAMM motif involved in zinc ion coordination. Poh1 is a regulator of c-Jun, an important regulator of cell proliferation, differentiation, survival and death. JAB1 is a component of the COP9 signalosome (CSN), a regulatory particle of the ubiquitin (Ub)/26S proteasome system occurring in all eukaryotic cells; it cleaves the ubiquitin-like protein NEDD8 from the cullin subunit of the SCF (Skp1, Cullins, F-box proteins) family of E3 ubiquitin ligases. AMSH (associated molecule with the SH3 domain of STAM, also known as STAMBP), a member of JAMM/MPN+ deubiquitinases (DUBs), specifically cleaves Lys 63-linked polyubiquitin (poly-Ub) chains, thus facilitating the recycling and subsequent trafficking of receptors to the cell surface. Similarly, BRCC36, part of the nuclear complex that includes BRCA1 protein and is targeted to DNA damage foci after irradiation, specifically disassembles K63-linked polyUb. BRCC36 is aberrantly expressed in sporadic breast tumors, indicative of a potential role in the pathogenesis of the disease. Some variants of the JAB1/MPN domains lack key residues in their JAMM motif and are unable to coordinate a metal ion. Comparisons of key catalytic and metal binding residues explain why the MPN-containing proteins Mov34/PSMD7, Rpn8, CSN6, Prp8p, and the translation initiation factor 3 subunits f (p47) and h (p40) do not show catalytic isopeptidase activity. It has been proposed that the MPN domain in these proteins has a primarily structural function.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1099511047  18 SPGPLALKIAGRIAEFFPDAVLIMLDNQKLVPQPRVPPVIVLENQGLRWVPKDKNLVMWRDWEESRQMVGALLEDRAHQH 97
Cdd:cd08060    86 SPSPVAKKIADKIAENFSNACLLMVDNEKLTLDCKGNALVVYKDKGGRWKVKELRGINLLLWESANEILSALLSSKAYRN 165

                          90
                  ....*....|....*..
gi 1099511047  98 LVDFDCHLDDIRQDWTN 114
Cdd:cd08060   166 LVDFDDHLDDISLDWLN 182

Mov34/MPN/PAD-1 family: UPF0172 family of unknown function includes neighbor of COX4 (Noc4p); This family includes Noc4p (neighbor of COX4; neighbor of Cytochrome c Oxidase 4; nucleolar complex associated 4 homolog) which belongs to the family of unknown function, UPF0172, with MPN/JAMM-like domains. Proteins in this family are homologs of the NOC4 gene which is conserved in eukaryotic members including human, dog, mouse, rat, chicken, zebrafish, fruit fly, mosquito, S.pombe, K.lactis, E.gossypii, M.grisea, N.crassa, A.thaliana, and rice. NOC4 highly expressed in the pancreas and moderately in liver, heart, lung, kidney, brain, skeletal muscle, and placenta. This nucleolar protein forms a complex with Nop14p that mediates maturation and nuclear export of 40S ribosomal subunits. This family of eukaryotic MPN-like domains lacks the key residues that coordinate a metal ion and therefore does not show catalytic isopeptidase activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1099511047  18 SPGPLALKIAGRIAEFFPDAVLIMLDNQKLVPQPRVPPVIVLENQGLRWVPKDKNLVMWRDWEESRQMVGALLEDRAHQH 97
Cdd:cd08060    86 SPSPVAKKIADKIAENFSNACLLMVDNEKLTLDCKGNALVVYKDKGGRWKVKELRGINLLLWESANEILSALLSSKAYRN 165

                          90
                  ....*....|....*..
gi 1099511047  98 LVDFDCHLDDIRQDWTN 114
Cdd:cd08060   166 LVDFDDHLDDISLDWLN 182

Mov34/MPN/PAD-1 family: UPF0172 family of unknown function includes neighbor of COX4 (Noc4p); This family includes Noc4p (neighbor of COX4; neighbor of Cytochrome c Oxidase 4; nucleolar complex associated 4 homolog) which belongs to the family of unknown function, UPF0172, with MPN/JAMM-like domains. Proteins in this family are homologs of the NOC4 gene which is conserved in eukaryotic members including human, dog, mouse, rat, chicken, zebrafish, fruit fly, mosquito, S.pombe, K.lactis, E.gossypii, M.grisea, N.crassa, A.thaliana, and rice. NOC4 highly expressed in the pancreas and moderately in liver, heart, lung, kidney, brain, skeletal muscle, and placenta. This nucleolar protein forms a complex with Nop14p that mediates maturation and nuclear export of 40S ribosomal subunits. This family of eukaryotic MPN-like domains lacks the key residues that coordinate a metal ion and therefore does not show catalytic isopeptidase activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1099511047  18 SPGPLALKIAGRIAEFFPDAVLIMLDNQKLVPQPRVPPVIVLENQGLRWVPKDKNLVMWRDWEESRQMVGALLEDRAHQH 97
Cdd:cd08060    86 SPSPVAKKIADKIAENFSNACLLMVDNEKLTLDCKGNALVVYKDKGGRWKVKELRGINLLLWESANEILSALLSSKAYRN 165

                          90
                  ....*....|....*..
gi 1099511047  98 LVDFDCHLDDIRQDWTN 114
Cdd:cd08060   166 LVDFDDHLDDISLDWLN 182