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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        2 VDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--MLKQT 79
Cdd:cd08069   6 PDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQT 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       80 GRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQTTSNL 158
Cdd:cd08069  84 GRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQTTSNI 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c      159 GHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNKAVEE 238
Cdd:cd08069 162 GHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQ 238

                       250       260       270
                ....*....|....*....|....*....|
5VHI_c      239 EDKMTPEQLAIKNVGKQD-----PKRHLEE 263
Cdd:cd08069 239 EERLTGEELDIANVGKLDkardsSKIHLEE 268

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        2 VDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--MLKQT 79
Cdd:cd08069   6 PDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQT 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       80 GRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQTTSNL 158
Cdd:cd08069  84 GRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQTTSNI 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c      159 GHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNKAVEE 238
Cdd:cd08069 162 GHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQ 238

                       250       260       270
                ....*....|....*....|....*....|
5VHI_c      239 EDKMTPEQLAIKNVGKQD-----PKRHLEE 263
Cdd:cd08069 239 EERLTGEELDIANVGKLDkardsSKIHLEE 268

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c          3 DTAEQVYISSLALLKMLKHGRAGVPM--EVMGLMLGEFVDDYTVRVIDVFAMPQSGTGVSVEAVDPVFQA--KMLDMLKQ 78
Cdd:pfam01398   1 SSVRTVIIHPLVLLKILDHANRGGKIgeEVMGVLLGKLEGDGTIEITNSFALPQEETEDDVNAVALDQEYmeNMHEMLKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
5VHI_c         79 TGRPEMVVGWYHSHPGFgCWLSGVDINTQQSFEALSER 116
Cdd:pfam01398  81 VNRKEEVVGWYHTHPGL-CWLSSVDVHTHALYQRMIPE 117

26S proteasome regulatory subunit; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c         3 DTAEQVYISSLALLKMLKHGR---AGVPMEVMGLMLGEFVDDyTVRVIDVFAMP--QSGTGVSVEAVDPVFQAKMLDMLK 77
Cdd:PLN03246   3 RGIEKVVVHPLVLLSIVDHYNrvaKDTRKRVVGVLLGSSFRG-RVDVTNSFAVPfeEDDKDPSIWFLDHNYLESMFGMFK 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
5VHI_c        78 QTGRPEMVVGWYHSHPGfgcwLSGVDINTQQSFEALSERAVAVVVD 123
Cdd:PLN03246  82 RINAKEHVVGWYSTGPK----LRENDLDIHELFNDYVPNPVLVIID 123

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        2 VDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--MLKQT 79
Cdd:cd08069   6 PDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQT 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       80 GRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQTTSNL 158
Cdd:cd08069  84 GRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQTTSNI 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c      159 GHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNKAVEE 238
Cdd:cd08069 162 GHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQ 238

                       250       260       270
                ....*....|....*....|....*....|
5VHI_c      239 EDKMTPEQLAIKNVGKQD-----PKRHLEE 263
Cdd:cd08069 239 EERLTGEELDIANVGKLDkardsSKIHLEE 268

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c           7 QVYISSLALLKMLKHGRAGVPMEVMGLMLGEFVDDyTVRVIDVFAMPQSGTGVSVEAVDPVFQAKMLDMLKQTGRPEMVV 86
Cdd:smart00232   1 EVKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKD-RPEVKEVFAVPNEPQDDSVQEYDEDYSHLMDEELKKVNKDLEIV 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
5VHI_c          87 GWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQSVKGKVVIDAFRLINA 142
Cdd:smart00232  80 GWYHSHPDESPFPSEVDVATHESYQAPWPISVVLIVDPIKSFQGRLSLRAFRLTPE 135

Mpr1p, Pad1p N-terminal (MPN) domains without catalytic isopeptidase activity, found in eIF2h; Eukaryotic translation initiation factor 3 (eIF3) subunit h (eIF3h; eIF3 subunit 3; eIF3S3; eIF3-gamma; eIF3-p40) 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.Together with eIF3e and eIF3f, eIF3h stabilizes the eIF3 complex. Results suggest that eIF3h regulates cell growth and viability, and that over-expression of the gene may provide growth advantage to prostate, breast, and liver cancer cells. For example, EIF3h gene amplification is common in late-stage prostate cancer suggesting that it may be functionally involved in the progression of the disease. It has been shown that coamplification of MYC, a well characterized oncogene involved in cell growth, differentiation, and apoptosis, and EIF3h in patients with non-small cell lung cancer (NSCLC) improves survival if treated with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), Gefitinib. Plant eIF3h is implicated in translation of specific mRNAs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        6 EQVYISSLALLKMLKHGRAGVPMEVMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVEAVDPV--FQAKMLDMLKQTGRPE 83
Cdd:cd08065   1 TSVQIDGLVVLKIIKHCKEELPELVQGQLLG-LDVGGTLEVTNCFPFPKSEEDDSDRADEDIadYQLEMMRLLREVNVDH 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
5VHI_c       84 MVVGWYHSHPgFGCWLSGVDINTQQSFEALSERAVAVVVDPIQSVKGKVVIDAFRL 139
Cdd:cd08065  80 NHVGWYQSTY-LGSFFTRDLIETQYNYQEAIEESVVLVYDPSKTSQGSLSLKAYRL 134

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        8 VYISSLALLKMLKH-GRAGVPME-VMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVeAVDPVFQAKMLDMLKQTGRPEMV 85
Cdd:cd08057   1 VQLHPLVLLNISDHyTRRKYGIKrVIGVLLG-YVDGDKIEVTNSFELPFDEEEESI-FIDTEYLEKRYNLHKKVYPQEKI 78

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
5VHI_c       86 VGWYHSHPGFGCWLSGVDINTQQSFEALSERA-VAVVVDPI-QSVKGKVVIDAFRLINANMMV 146
Cdd:cd08057  79 VGWYSIGSNNSNEISKSDNSLHSQFSLISEENpLILILDPSlQSDSEKLEISTFTSAQREENG 141

Proteasome lid subunit RPN8/RPN11, contains Jab1/MPN domain metalloenzyme (JAMM) motif [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c        7 QVYISSLALLKMLKHGRAGVPMEVMGLMLGEFVDDytVRVIDVFAMPQSGTGVSVE-AVDPVFQAKMLDMLKQTGRPemV 85
Cdd:COG1310   1 MLVLPRELLDAILAHAEAAYPEECCGLLLGKGGGD--KRVTRVYPARNVAESPETRfEIDPEDLLAAEREARERGLE--I 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
5VHI_c       86 VGWYHSHPGFGCWLSGVDIntqqsFEALSERAVAVVVdpiqSV-KGKVVIDAFRLIN 141
Cdd:COG1310  77 VGIYHSHPDGPAYPSETDR-----AQAAWPGLPYLIV----SLpDGGPELRAWRLRD 124

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       15 LLKMLKHGRAGVPMEVMGLMLGEFvdDYTVRVID-VFAMPQSGTGVSVEAVdpvfqAKMLDMLKQTGRPEMVVGWYHSHP 93
Cdd:cd07767   1 LKMFLDAAKSINGKEVIGLLYGSK--TKKVLDVDeVIAVPFDEGDKDDNVW-----FLMYLDFKKLNAGLRIVGWYHTHP 73

                        90       100       110
                ....*....|....*....|....*....|.
5VHI_c       94 GFGCWLSGVDINTQQSFEALSERAVAVVVDP 124
Cdd:cd07767  74 KPSCFLSPNDLATHELFQRYFPEKVMIIVDV 104

Mpr1p, Pad1p N-terminal (MPN) domains with catalytic isopeptidase activity (metal-binding); This family contains archaeal and bacterial MPN (also known as Mov34, PAD-1, JAMM, JAB, MPN+)-like domains. These domains contain the signature JAB1/MPN/Mov34 metalloenzyme (JAMM) motif, EXnHS/THX7SXXD, which is involved in zinc ion coordination and provides the active site for isopeptidase activity for the release of ubiquitin from ubiquitinated proteins (thus having deubiquitinating (DUB) activity) that are tagged for degradation. The JAMM proteins likely hydrolyze ubiquitin conjugates in a manner similar to thermolysin, in which the zinc-polarized aqua ligand serves as the nucleophile, compared with the classical DUBs that do so with a cysteine residue in the active site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       14 ALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVE-AVDPVFQAKMLDMLKQTGRPemVVGWYHSH 92
Cdd:cd08070   3 LLEAILAHAEAEYPEECCGLLLGK-GGGVTAIVTEVYPVRNVAESPRRRfEIDPAEQLAAQREARERGLE--VVGIYHSH 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
5VHI_c       93 PGFGCWLSGVDINtqqsfEALSERAVAVvvdpIQSVKGKV-VIDAFRL 139
Cdd:cd08070  80 PDGPARPSETDLR-----LAWPPGVSYL----IVSLAGGApELRAWRL 118

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
                ....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       30 VMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVeAVDPVFQAKMLDMLKQTGRPEMVVGWY 89
Cdd:cd08064  25 VIGTLLG-TRSEGEVEITNCFAVPHNESEDQV-AVDMEYHRTMYELHQKVNPKEVIVGWY 82

Mpr1p, Pad1p N-terminal (MPN) domains with catalytic isopeptidase activity (metal-binding); prokaryotic; This family contains bacterial and archaeal MPN (also known as Mov34, PAD-1, JAMM, JAB, MPN+)-like domains. These catalytically active domains contain the signature JAB1/MPN/Mov34 metalloenzyme (JAMM) motif, EXnHS/THX7SXXD, which is involved in zinc ion coordination and provides the active site for isopeptidase activity for the release of ubiquitin from ubiquitinated proteins (thus having deubiquitinating (DUB) activity) that are tagged for degradation. The JAMM proteins likely hydrolyze ubiquitin conjugates in a manner similar to thermolysin, in which the zinc-polarized aqua ligand serves as the nucleophile, compared with the classical DUBs that do so with a cysteine residue in the active site.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
5VHI_c       18 MLKHGRAGVPMEVMGLMLGEfVDDYTVRVIdvfAMPQSGTGVSVEavdpvfqaKMLDMLKQTGRpemVVGWYHSHPGFGC 97
Cdd:cd08059   6 ILVHAKDAHPDEFCGFLSGS-KDNVMDELI---FLPFVSGSVSAV--------IDLAALEIGMK---VVGLVHSHPSGSC 70

                        90
                ....*....|
5VHI_c       98 WLSGVDINTQ 107
Cdd:cd08059  71 RPSEADLSLF 80