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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119   3 EVIVHPLVLLSAVDHYKR--KGT-KRVAGILLGD-DDGEIHITESFACIFEEDEDG---WFMDTSYIRSMFDLFYKVNHK 75
Cdd:cd08062   2 KVVVHPLVLLSVVDHYNRvaKGTsKRVVGVLLGSwKKGVLDVTNSFAVPFEEDEKDpsvWFLDHNYLENMYGMFKKVNAK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119  76 LKVMGWYHTGPRMYENDLDITRSLGSFVESPFLAIINVHLGENDLPVQTFKLDEQDE---------FVHVGCSIEAEEAE 146
Cdd:cd08062  82 EKIVGWYSTGPKLRPNDLDINELFRRYCPNPVLVIIDVRPKDLGLPTEAYIAVEEVHddgtptsktFVHVPSEIGAEEAE 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119 147 EVGVEHLIRDIREEASGSIAARINGIKESLAVYRGVLGEIRSYLNDVISGDIHLNQEIINLCQEIINSTPKLERP----- 221
Cdd:cd08062 162 EVGVEHLLRDIKDVTVSTLSTRVTNKLNSLKGLQSKLKEIKDYLQLVVEGKLPINHQIIYNLQDIFNLLPNLNLPelvka 241

                       250       260       270
                ....*....|....*....|....*....|...
gi 19074119 222 ----LDENLSDCYVSVLAKTVVALNDLRKNRLE 250
Cdd:cd08062 242 favkTNDQMLVIYLSSLIRSVIALHNLINNKIA 274

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in 19S proteasomal subunits Rpn7 and Rpn8; This family includes lid subunits of the 26 S proteasome regulatory particles, Rpn7 (PSMD7; proteasome 26S non-ATPase subunit 7; p44), and Rpn8 (PSMD8; proteasome 26S non-ATPase subunit 8; p40; Mov34). Rpn7 is known to be critical for the integrity of the 26 S proteasome complex by establishing a correct lid structure. It is necessary for the incorporation/anchoring of Rpn3 and Rpn12 to the lid and essential for viability and normal mitosis. Rpn7 and Rpn8 are ATP-independent components of the 19S regulator subunit, and contain the MPN structural motif on its N-terminal region. However, while they show a typical MPN metalloprotease fold, they lack the canonical JAMM motif, and therefore do not show catalytic isopeptidase activity. It is suggested that Rpn7 function is primarily structural.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119   3 EVIVHPLVLLSAVDHYKR--KGT-KRVAGILLGD-DDGEIHITESFACIFEEDEDG---WFMDTSYIRSMFDLFYKVNHK 75
Cdd:cd08062   2 KVVVHPLVLLSVVDHYNRvaKGTsKRVVGVLLGSwKKGVLDVTNSFAVPFEEDEKDpsvWFLDHNYLENMYGMFKKVNAK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119  76 LKVMGWYHTGPRMYENDLDITRSLGSFVESPFLAIINVHLGENDLPVQTFKLDEQDE---------FVHVGCSIEAEEAE 146
Cdd:cd08062  82 EKIVGWYSTGPKLRPNDLDINELFRRYCPNPVLVIIDVRPKDLGLPTEAYIAVEEVHddgtptsktFVHVPSEIGAEEAE 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119 147 EVGVEHLIRDIREEASGSIAARINGIKESLAVYRGVLGEIRSYLNDVISGDIHLNQEIINLCQEIINSTPKLERP----- 221
Cdd:cd08062 162 EVGVEHLLRDIKDVTVSTLSTRVTNKLNSLKGLQSKLKEIKDYLQLVVEGKLPINHQIIYNLQDIFNLLPNLNLPelvka 241

                       250       260       270
                ....*....|....*....|....*....|...
gi 19074119 222 ----LDENLSDCYVSVLAKTVVALNDLRKNRLE 250
Cdd:cd08062 242 favkTNDQMLVIYLSSLIRSVIALHNLINNKIA 274

JAB1/Mov34/MPN/PAD-1 ubiquitin protease; Members of this family are found in proteasome regulatory subunits, eukaryotic initiation factor 3 (eIF3) subunits and regulators of transcription factors. This family is also known as the MPN domain and PAD-1-like domain, JABP1 domain or JAMM domain. These are metalloenzymes that function as the ubiquitin isopeptidase/ deubiquitinase in the ubiquitin-based signalling and protein turnover pathways in eukaryotes. Versions of the domain in prokaryotic cognates of the ubiquitin-modification pathway are shown to have a similar role, and the archael protein from Haloferax volcanii is found to cleave ubiquitin-like small archaeal modifier proteins (SAMP1/2) from protein conjugates.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119     4 VIVHPLVLLSAVDHYKR--KGTKRVAGILLG--DDDGEIHITESFACIFEEDED---GWFMDTSYIRSMFDLFYKVNHKL 76
Cdd:pfam01398   6 VIIHPLVLLKILDHANRggKIGEEVMGVLLGklEGDGTIEITNSFALPQEETEDdvnAVALDQEYMENMHEMLKKVNRKE 85

                          90
                  ....*....|
gi 19074119    77 KVMGWYHTGP 86
Cdd:pfam01398  86 EVVGWYHTHP 95

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in 19S proteasomal subunits Rpn7 and Rpn8; This family includes lid subunits of the 26 S proteasome regulatory particles, Rpn7 (PSMD7; proteasome 26S non-ATPase subunit 7; p44), and Rpn8 (PSMD8; proteasome 26S non-ATPase subunit 8; p40; Mov34). Rpn7 is known to be critical for the integrity of the 26 S proteasome complex by establishing a correct lid structure. It is necessary for the incorporation/anchoring of Rpn3 and Rpn12 to the lid and essential for viability and normal mitosis. Rpn7 and Rpn8 are ATP-independent components of the 19S regulator subunit, and contain the MPN structural motif on its N-terminal region. However, while they show a typical MPN metalloprotease fold, they lack the canonical JAMM motif, and therefore do not show catalytic isopeptidase activity. It is suggested that Rpn7 function is primarily structural.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119   3 EVIVHPLVLLSAVDHYKR--KGT-KRVAGILLGD-DDGEIHITESFACIFEEDEDG---WFMDTSYIRSMFDLFYKVNHK 75
Cdd:cd08062   2 KVVVHPLVLLSVVDHYNRvaKGTsKRVVGVLLGSwKKGVLDVTNSFAVPFEEDEKDpsvWFLDHNYLENMYGMFKKVNAK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119  76 LKVMGWYHTGPRMYENDLDITRSLGSFVESPFLAIINVHLGENDLPVQTFKLDEQDE---------FVHVGCSIEAEEAE 146
Cdd:cd08062  82 EKIVGWYSTGPKLRPNDLDINELFRRYCPNPVLVIIDVRPKDLGLPTEAYIAVEEVHddgtptsktFVHVPSEIGAEEAE 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119 147 EVGVEHLIRDIREEASGSIAARINGIKESLAVYRGVLGEIRSYLNDVISGDIHLNQEIINLCQEIINSTPKLERP----- 221
Cdd:cd08062 162 EVGVEHLLRDIKDVTVSTLSTRVTNKLNSLKGLQSKLKEIKDYLQLVVEGKLPINHQIIYNLQDIFNLLPNLNLPelvka 241

                       250       260       270
                ....*....|....*....|....*....|...
gi 19074119 222 ----LDENLSDCYVSVLAKTVVALNDLRKNRLE 250
Cdd:cd08062 242 favkTNDQMLVIYLSSLIRSVIALHNLINNKIA 274

JAB1/Mov34/MPN/PAD-1 ubiquitin protease; Members of this family are found in proteasome regulatory subunits, eukaryotic initiation factor 3 (eIF3) subunits and regulators of transcription factors. This family is also known as the MPN domain and PAD-1-like domain, JABP1 domain or JAMM domain. These are metalloenzymes that function as the ubiquitin isopeptidase/ deubiquitinase in the ubiquitin-based signalling and protein turnover pathways in eukaryotes. Versions of the domain in prokaryotic cognates of the ubiquitin-modification pathway are shown to have a similar role, and the archael protein from Haloferax volcanii is found to cleave ubiquitin-like small archaeal modifier proteins (SAMP1/2) from protein conjugates.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119     4 VIVHPLVLLSAVDHYKR--KGTKRVAGILLG--DDDGEIHITESFACIFEEDED---GWFMDTSYIRSMFDLFYKVNHKL 76
Cdd:pfam01398   6 VIIHPLVLLKILDHANRggKIGEEVMGVLLGklEGDGTIEITNSFALPQEETEDdvnAVALDQEYMENMHEMLKKVNRKE 85

                          90
                  ....*....|
gi 19074119    77 KVMGWYHTGP 86
Cdd:pfam01398  86 EVVGWYHTHP 95

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity (non metal-binding); eukaryotic; This family contains MPN (also known as Mov34, PAD-1, JAMM, JAB, MPN+) domains variants lacking key residues in the JAB1/MPN/Mov34 metalloenzyme (JAMM) motif and are unable to coordinate a metal ion. Comparisons of key catalytic and metal binding residues explain why the MPN-containing proteins Rpn7/PSMD7, Rpn8/PSMD8, CSN6, Prp8p, and the translation initiation factor 3 subunits f and h do not show catalytic isopeptidase activity. It has been proposed that the MPN domain in these proteins has a primarily structural function. Rpn7 is known to be critical for the integrity of the 26S proteasome complex by establishing a correct lid structure. It is necessary for the incorporation/anchoring of Rpn3 and Rpn12 to the lid and essential for viability and normal mitosis. CSN6 is a highly conserved protein complex with diverse functions, including several important intracellular pathways such as the ubiquitin/proteasome system, DNA repair, cell cycle, developmental changes, and some aspects of immune responses. It cleaves ubiquitin-like protein Nedd8 (neural precursor cell expressed, developmentally downregulated 8)) in the cullin 1 in cells. EIF3f s a potent inhibitor of HIV-1 replication as well as an important negative regulator of cell growth and proliferation. EIF3h regulates cell growth and viability, and that over-expression of the gene may provide growth advantage to prostate, breast, and liver cancer cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119   4 VIVHPLVLLSAVDHYKRK--GTKRVAGILLG-DDDGEIHITESFACIFEEDEDGWFMDTSYIRSMFDLFYKVNHKLKVMG 80
Cdd:cd08057   1 VQLHPLVLLNISDHYTRRkyGIKRVIGVLLGyVDGDKIEVTNSFELPFDEEEESIFIDTEYLEKRYNLHKKVYPQEKIVG 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 19074119  81 WYHTG----PRMYENDLDITRSLGSFVESPFLA-IINVHLG--ENDLPVQTFKLDEQDEFVH 135
Cdd:cd08057  81 WYSIGsnnsNEISKSDNSLHSQFSLISEENPLIlILDPSLQsdSEKLEISTFTSAQREENGA 142

JAB/MPN domain; Domain in Jun kinase activation domain binding protein and proteasomal subunits. Domain at Mpr1p and Pad1p N-termini. Domain of unknown function.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119      3 EVIVHPLVLLSAVDHYKRKGTKRVAGILLGDDDGE-IHITESFACIFEEDEDG-WFMDTSYIRSMFDLFYKVNHKLKVMG 80
Cdd:smart00232   1 EVKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKDrPEVKEVFAVPNEPQDDSvQEYDEDYSHLMDEELKKVNKDLEIVG 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 19074119     81 WYHTGP----RMYENDLDITRSLGSFVESPFLAIINVH-LGENDLPVQTFKL 127
Cdd:smart00232  81 WYHSHPdespFPSEVDVATHESYQAPWPISVVLIVDPIkSFQGRLSLRAFRL 132

Maintenance of mitochondrial structure and function; This is C-terminal to the Mov24 region of the yeast proteasomal subunit Rpn11 and seems likely to regulate the mitochondrial fission and tubulation processes, ie the outer mitochondrial membrane proteins. This function appears to be unrelated to the proteasome activity of the N-terminal region.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 19074119   152 HLIR-DIReeasgSIAARINGIKESLAVYRGVLGEIRSYLNDVISGDIHLNQEIINLCQEIIN 213
Cdd:pfam13012   9 HLARpDIK-----SLSSDLERQYYSLKMLQDRLDLILKYVEDVLDGELPPDHAIGRYLQDLLA 66

Mov34/MPN/PAD-1 family: proteasomal regulatory protein Rpn11 and signalosome complex subunit CSN5; This family contains proteasomal regulatory protein Rpn11 (26S proteasome regulatory subunit rpn11; PAD1; POH1; RPN11; PSMD14; Rpn11 subunit of the 19S-proteasome; regulatory particle number 11) and signalosomal CSN5 (COP9 signalosome complex subunit 5; COP9 complex homolog subunit 5; c-Jun activation domain-binding protein-1; CSN5/JAB1; JAB1). COP9 signalosome (CSN) and the proteasome lid are paralogous complexes and their respective subunits CSN5 and Rpn11 are most closely related between the two complexes, both containing the conserved JAMM (JAB1/MPN/Mov34 metalloenzyme) motif involved in zinc ion coordination and providing the active site for isopeptidase activity. Rpn11 is responsible for substrate deubiquitination during proteasomal degradation. It is essential for maintaining a correct cell cycle and normal mitochondrial morphology and physiology; mutations in Rpn11 cause cell cycle and mitochondrial defects, temperature sensitivity and sensitivity to DNA damaging reagents such as UV. It has been shown that the C-terminal region of Rpn11 is involved in the regulation of the mitochondrial fission and tubulation processes. CSN5, one of the eight subunits of CSN, is critical for nuclear export and the degradation of several tumor suppressor proteins, including p53, p27, and Smad4. Its MPN+ domain is critical for the physical interaction of RUNX3 and Jab1. It has been suggested that the direct interaction of CSN5/JAB1 with p27 provides p27 with a leucine-rich nuclear export signal (NES), which is required for binding to chromosomal region maintenance 1 (CRM1), and facilitates nuclear export. The over-expression of CSN5/JAB1 also has been implicated in cancer initiation and progression, including cancer of the lung, pancreas, mouth, thyroid, and breast, suggesting that the oncogenic activity of CSN5 is associated with the down-regulation of RUNX3.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19074119   4 VIVHPLVLLSAVDHYKRKGTKRVAGILLGD-DDGEIHITESFACIFEEDEDGWFMDTSYIRSMFDLFY--KVNHKLKVMG 80
Cdd:cd08069  12 VYISSLALLKMLKHARAGGPIEVMGLMLGKvDDYTIIVVDVFALPVEGTETRVNAQDEFQEYMVQYEMlkQTGRPENVVG 91

                ....*.
gi 19074119  81 WYHTGP 86
Cdd:cd08069  92 WYHSHP 97