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 71649286  24 MPIRLQPLVILNITQHATRVWQHSAtSTTATALGVLLGrpTVDGGT-EIMSSFEVVgYETGNTAARSVDWRAVRSKKERL 102
Cdd:cd08063   1 LSVKLHPLVILNISDHITRHRAQSQ-SEPPRVVGALLG--QQDGREiEIENSFELK-YDTNEDGEIVLDKEFLETRLEQF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 103 AEVFAELVVVGWYGVGRTreDAVQCSSIMHVPLLDVfgdvpNGVMLALMVDRAPPASLATLPVHLFEATTSRDGVrhtag 182
Cdd:cd08063  77 KQVFKDLDFVGWYTTGPG--GPTESDLPIHKQILEI-----NESPVLLLLDPEANASGKDLPVTIYESVLELVDG----- 144

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 183 eeqrgqEAIQRHRSHNYNSEISPCTaahgsRIlchnegaprttvclrnvrfltgsddmaqigigaAMSTIGPGNRSGGHE 262
Cdd:cd08063 145 ------EATLRFRELPYTIETGEAE-----RI---------------------------------GVDHVARGGASGSSE 180

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 263 GGTVSSHPQRVKRSLLLLKRRVVLVLEHLRAIESGCVaCPAPDVLRHVAKACAMLPVSTHDASlcpvaaviipTTAADEE 342
Cdd:cd08063 181 KSTVAAHLQAQHNAIKMLNSRVELILEYLKAVPVGEV-PPDHSILRSISALCSRLPVLKSEAF----------REELLAE 249

                       330       340       350
                ....*....|....*....|....*....|....*
gi 71649286 343 VCGALAITLLSLETKCALALCELVRAQEEGPAVGR 377
Cdd:cd08063 250 YNDVLLVAYLATLTKGCNTLNELVDKFNVVYDRKG 284

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in COP9 signalosome complex subunit 6; CSN6 (COP9 signalosome subunit 6; COP9 subunit 6; MOV34 homolog, 34 kD) is one of the eight subunits of COP9 signalosome, 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. CSN6 is an MPN-domain protein that directly interacts with the MPN+-domain subunit CSN5. It is cleaved during apoptosis by activated caspases. CSN6 processing occurs in CSN/CRL (cullin-RING Ub ligase) complexes and is followed by the cleavage of Rbx1, the direct interaction partner of CSN6. CSN6 cleavage enhances CSN-mediated deneddylating activity (i.e. cleavage of ubiquitin-like protein Nedd8 (neural precursor cell expressed, developmentally downregulated 8)) in the cullin 1 in cells. The cleavage of Rbx1 and increased deneddylation of cullins inactivate CRLs and presumably stabilize pro-apoptotic factors for final apoptotic steps. While CSN6 shows a typical MPN metalloprotease fold, it lacks the canonical JAMM motif, and therefore does not show catalytic isopeptidase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286  24 MPIRLQPLVILNITQHATRVWQHSAtSTTATALGVLLGrpTVDGGT-EIMSSFEVVgYETGNTAARSVDWRAVRSKKERL 102
Cdd:cd08063   1 LSVKLHPLVILNISDHITRHRAQSQ-SEPPRVVGALLG--QQDGREiEIENSFELK-YDTNEDGEIVLDKEFLETRLEQF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 103 AEVFAELVVVGWYGVGRTreDAVQCSSIMHVPLLDVfgdvpNGVMLALMVDRAPPASLATLPVHLFEATTSRDGVrhtag 182
Cdd:cd08063  77 KQVFKDLDFVGWYTTGPG--GPTESDLPIHKQILEI-----NESPVLLLLDPEANASGKDLPVTIYESVLELVDG----- 144

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 183 eeqrgqEAIQRHRSHNYNSEISPCTaahgsRIlchnegaprttvclrnvrfltgsddmaqigigaAMSTIGPGNRSGGHE 262
Cdd:cd08063 145 ------EATLRFRELPYTIETGEAE-----RI---------------------------------GVDHVARGGASGSSE 180

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 263 GGTVSSHPQRVKRSLLLLKRRVVLVLEHLRAIESGCVaCPAPDVLRHVAKACAMLPVSTHDASlcpvaaviipTTAADEE 342
Cdd:cd08063 181 KSTVAAHLQAQHNAIKMLNSRVELILEYLKAVPVGEV-PPDHSILRSISALCSRLPVLKSEAF----------REELLAE 249

                       330       340       350
                ....*....|....*....|....*....|....*
gi 71649286 343 VCGALAITLLSLETKCALALCELVRAQEEGPAVGR 377
Cdd:cd08063 250 YNDVLLVAYLATLTKGCNTLNELVDKFNVVYDRKG 284

26S proteasome regulatory subunit; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286   28 LQPLVILNITQHATRVwqhsATSTTATALGVLLG---RPTVDggteIMSSFEVVGYETGNTAarSVdWRAVRSKKERLAE 104
Cdd:PLN03246  10 VHPLVLLSIVDHYNRV----AKDTRKRVVGVLLGssfRGRVD----VTNSFAVPFEEDDKDP--SI-WFLDHNYLESMFG 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286  105 VF----AELVVVGWYGVG-RTREDAVQCSSIMHvplldvfGDVPNGVMlaLMVDRAPpaSLATLPvhlFEATTSRDGVRH 179
Cdd:PLN03246  79 MFkrinAKEHVVGWYSTGpKLRENDLDIHELFN-------DYVPNPVL--VIIDVQP--KELGIP---TKAYYAVEEVKE 144

                 ....*..
gi 71649286  180 TAGEEQR 186
Cdd:PLN03246 145 NATQKSQ 151

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in COP9 signalosome complex subunit 6; CSN6 (COP9 signalosome subunit 6; COP9 subunit 6; MOV34 homolog, 34 kD) is one of the eight subunits of COP9 signalosome, 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. CSN6 is an MPN-domain protein that directly interacts with the MPN+-domain subunit CSN5. It is cleaved during apoptosis by activated caspases. CSN6 processing occurs in CSN/CRL (cullin-RING Ub ligase) complexes and is followed by the cleavage of Rbx1, the direct interaction partner of CSN6. CSN6 cleavage enhances CSN-mediated deneddylating activity (i.e. cleavage of ubiquitin-like protein Nedd8 (neural precursor cell expressed, developmentally downregulated 8)) in the cullin 1 in cells. The cleavage of Rbx1 and increased deneddylation of cullins inactivate CRLs and presumably stabilize pro-apoptotic factors for final apoptotic steps. While CSN6 shows a typical MPN metalloprotease fold, it lacks the canonical JAMM motif, and therefore does not show catalytic isopeptidase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286  24 MPIRLQPLVILNITQHATRVWQHSAtSTTATALGVLLGrpTVDGGT-EIMSSFEVVgYETGNTAARSVDWRAVRSKKERL 102
Cdd:cd08063   1 LSVKLHPLVILNISDHITRHRAQSQ-SEPPRVVGALLG--QQDGREiEIENSFELK-YDTNEDGEIVLDKEFLETRLEQF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 103 AEVFAELVVVGWYGVGRTreDAVQCSSIMHVPLLDVfgdvpNGVMLALMVDRAPPASLATLPVHLFEATTSRDGVrhtag 182
Cdd:cd08063  77 KQVFKDLDFVGWYTTGPG--GPTESDLPIHKQILEI-----NESPVLLLLDPEANASGKDLPVTIYESVLELVDG----- 144

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 183 eeqrgqEAIQRHRSHNYNSEISPCTaahgsRIlchnegaprttvclrnvrfltgsddmaqigigaAMSTIGPGNRSGGHE 262
Cdd:cd08063 145 ------EATLRFRELPYTIETGEAE-----RI---------------------------------GVDHVARGGASGSSE 180

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286 263 GGTVSSHPQRVKRSLLLLKRRVVLVLEHLRAIESGCVaCPAPDVLRHVAKACAMLPVSTHDASlcpvaaviipTTAADEE 342
Cdd:cd08063 181 KSTVAAHLQAQHNAIKMLNSRVELILEYLKAVPVGEV-PPDHSILRSISALCSRLPVLKSEAF----------REELLAE 249

                       330       340       350
                ....*....|....*....|....*....|....*
gi 71649286 343 VCGALAITLLSLETKCALALCELVRAQEEGPAVGR 377
Cdd:cd08063 250 YNDVLLVAYLATLTKGCNTLNELVDKFNVVYDRKG 284

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 71649286  26 IRLQPLVILNITQHATRVwqhsaTSTTATALGVLLGRptVDGGT-EIMSSFEVvgyETGNTAARSVDWRAVRSKKERL-A 103
Cdd:cd08057   1 VQLHPLVLLNISDHYTRR-----KYGIKRVIGVLLGY--VDGDKiEVTNSFEL---PFDEEEESIFIDTEYLEKRYNLhK 70

                        90
                ....*....|....*
gi 71649286 104 EVFAELVVVGWYGVG 118
Cdd:cd08057  71 KVYPQEKIVGWYSIG 85

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in eIF3f; Eukaryotic translation initiation factor 3 (eIF3) subunit F (eIF3F; EIF3S5; eIF3-p47; eukaryotic translation initiation factor 3, subunit 5 epsilon, 47kDa; Mov34/MPN/PAD-1 family protein) is an evolutionarily non-conserved subunit of the functional core that comprises eIF3a, eIF3b, eIF3c, eIF3e, eIF3f, and eIF3h, and contains the MPN domain. However, it lacks the canonical JAMM motif, and therefore does not show catalytic isopeptidase activity. It has been shown that eIF3f mRNA expression is significantly decreased in many human tumors including pancreatic cancer and melanoma. EIF3f is a potent inhibitor of HIV-1 replication; it mediates restriction of HIV-1 expression through several factors including the serine/arginine-rich (SR) protein 9G8, and cyclin-dependent kinase 11 (CDK11). EIF3f phosphorylation by CDK11 is important in regulating its function in translation and apoptosis. It enhances its association with the core eIF3 subunits during apoptosis, suggesting that eIF3f may inhibit translation by increasing the binding to the eIF3 complex during apoptosis. Thus, eIF3f may be an important negative regulator of cell growth and proliferation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71649286  26 IRLQPLVILNITQHATRVwQHSATSttatALGVLLGrpTVDGGT-EIMSSFEVVGYETGNTAArsVDWRAVRSKKERLAE 104
Cdd:cd08064   1 VRVHPVVLFSILDSYERR-NEGQER----VIGTLLG--TRSEGEvEITNCFAVPHNESEDQVA--VDMEYHRTMYELHQK 71

                        90
                ....*....|....
gi 71649286 105 VFAELVVVGWYGVG 118
Cdd:cd08064  72 VNPKEVIVGWYATG 85