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 71043862  21 DAPAVDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--M 98
Cdd:cd08069   2 WKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  99 LKQTGRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQT 177
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQT 157

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862 178 TSNLGHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNK 257
Cdd:cd08069 158 TSNIGHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEK 234

                       250       260       270
                ....*....|....*....|....*....|....
gi 71043862 258 AVEEEDKMTPEQLAIKNVGKQD-----PKRHLEE 286
Cdd:cd08069 235 AEQQEERLTGEELDIANVGKLDkardsSKIHLEE 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  21 DAPAVDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--M 98
Cdd:cd08069   2 WKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  99 LKQTGRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQT 177
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQT 157

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862 178 TSNLGHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNK 257
Cdd:cd08069 158 TSNIGHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEK 234

                       250       260       270
                ....*....|....*....|....*....|....
gi 71043862 258 AVEEEDKMTPEQLAIKNVGKQD-----PKRHLEE 286
Cdd:cd08069 235 AEQQEERLTGEELDIANVGKLDkardsSKIHLEE 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862    26 DTAEQVYISSLALLKMLKHGRAGVPM--EVMGLMLGEFVDDYTVRVIDVFAMPQSGTGVSVEAVDPVFQA--KMLDMLKQ 101
Cdd:pfam01398   1 SSVRTVIIHPLVLLKILDHANRGGKIgeEVMGVLLGKLEGDGTIEITNSFALPQEETEDDVNAVALDQEYmeNMHEMLKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 71043862   102 TGRPEMVVGWYHSHPGFgCWLSGVDINTQQSFEALSER 139
Cdd:pfam01398  81 VNRKEEVVGWYHTHPGL-CWLSSVDVHTHALYQRMIPE 117

26S proteasome regulatory subunit; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862   26 DTAEQVYISSLALLKMLKHGR---AGVPMEVMGLMLGEFVDDyTVRVIDVFAMP--QSGTGVSVEAVDPVFQAKMLDMLK 100
Cdd:PLN03246   3 RGIEKVVVHPLVLLSIVDHYNrvaKDTRKRVVGVLLGSSFRG-RVDVTNSFAVPfeEDDKDPSIWFLDHNYLESMFGMFK 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 71043862  101 QTGRPEMVVGWYHSHPGfgcwLSGVDINTQQSFEALSERAVAVVVD 146
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  21 DAPAVDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVEAVDpVFQAKMLD--M 98
Cdd:cd08069   2 WKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  99 LKQTGRPEMVVGWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQS-VKGKVVIDAFRLINANMMVLghEPRQT 177
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPGYKPL--EPRQT 157

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862 178 TSNLGHLNKPSIQaLIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCkhNESVVKEMLELAKNYNK 257
Cdd:cd08069 158 TSNIGHLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEK 234

                       250       260       270
                ....*....|....*....|....*....|....
gi 71043862 258 AVEEEDKMTPEQLAIKNVGKQD-----PKRHLEE 286
Cdd:cd08069 235 AEQQEERLTGEELDIANVGKLDkardsSKIHLEE 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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862     30 QVYISSLALLKMLKHGRAGVPMEVMGLMLGEFVDDyTVRVIDVFAMPQSGTGVSVEAVDPVFQAKMLDMLKQTGRPEMVV 109
Cdd:smart00232   1 EVKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKD-RPEVKEVFAVPNEPQDDSVQEYDEDYSHLMDEELKKVNKDLEIV 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 71043862    110 GWYHSHPGFGCWLSGVDINTQQSFEALSERAVAVVVDPIQSVKGKVVIDAFRLINA 165
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  29 EQVYISSLALLKMLKHGRAGVPMEVMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVEAVDPV--FQAKMLDMLKQTGRPE 106
Cdd:cd08065   1 TSVQIDGLVVLKIIKHCKEELPELVQGQLLG-LDVGGTLEVTNCFPFPKSEEDDSDRADEDIadYQLEMMRLLREVNVDH 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 71043862 107 MVVGWYHSHPgFGCWLSGVDINTQQSFEALSERAVAVVVDPIQSVKGKVVIDAFRL 162
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  31 VYISSLALLKMLKH-GRAGVPME-VMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVeAVDPVFQAKMLDMLKQTGRPEMV 108
Cdd:cd08057   1 VQLHPLVLLNISDHyTRRKYGIKrVIGVLLG-YVDGDKIEVTNSFELPFDEEEESI-FIDTEYLEKRYNLHKKVYPQEKI 78

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71043862 109 VGWYHSHPGFGCWLSGVDINTQQSFEALSERA-VAVVVDPI-QSVKGKVVIDAFRLINANMMV 169
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  30 QVYISSLALLKMLKHGRAGVPMEVMGLMLGEFVDDytVRVIDVFAMPQSGTGVSVE-AVDPVFQAKMLDMLKQTGRPemV 108
Cdd:COG1310   1 MLVLPRELLDAILAHAEAAYPEECCGLLLGKGGGD--KRVTRVYPARNVAESPETRfEIDPEDLLAAEREARERGLE--I 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 71043862 109 VGWYHSHPGFGCWLSGVDIntqqsFEALSERAVAVVVdpiqSV-KGKVVIDAFRLIN 164
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  38 LLKMLKHGRAGVPMEVMGLMLGEFvdDYTVRVID-VFAMPQSGTGVSVEAVdpvfqAKMLDMLKQTGRPEMVVGWYHSHP 116
Cdd:cd07767   1 LKMFLDAAKSINGKEVIGLLYGSK--TKKVLDVDeVIAVPFDEGDKDDNVW-----FLMYLDFKKLNAGLRIVGWYHTHP 73

                        90       100       110
                ....*....|....*....|....*....|.
gi 71043862 117 GFGCWLSGVDINTQQSFEALSERAVAVVVDP 147
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  37 ALLKMLKHGRAGVPMEVMGLMLGEfVDDYTVRVIDVFAMPQSGTGVSVE-AVDPVFQAKMLDMLKQTGRPemVVGWYHSH 115
Cdd:cd08070   3 LLEAILAHAEAEYPEECCGLLLGK-GGGVTAIVTEVYPVRNVAESPRRRfEIDPAEQLAAQREARERGLE--VVGIYHSH 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 71043862 116 PGFGCWLSGVDINtqqsfEALSERAVAVvvdpIQSVKGKV-VIDAFRL 162
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
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  53 VMGLMLGeFVDDYTVRVIDVFAMPQSGTGVSVeAVDPVFQAKMLDMLKQTGRPEMVVGWY 112
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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71043862  41 MLKHGRAGVPMEVMGLMLGEfVDDYTVRVIdvfAMPQSGTGVSVEavdpvfqaKMLDMLKQTGRpemVVGWYHSHPGFGC 120
Cdd:cd08059   6 ILVHAKDAHPDEFCGFLSGS-KDNVMDELI---FLPFVSGSVSAV--------IDLAALEIGMK---VVGLVHSHPSGSC 70

                        90
                ....*....|
gi 71043862 121 WLSGVDINTQ 130
Cdd:cd08059  71 RPSEADLSLF 80