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 17137694  41 PWEKDPHFFKDIKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVNAQAQAYEYMTAYmEA 120
Cdd:cd08069   1 PWKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGKVDDYTIIVVDVFALPVEGTETRVNAQDEFQEYMVQY-EM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 121 AKEVGRMEHAVGWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVVDPVRTVSAGKVCLGAFRTYPKGYKP--PNEEPS 198
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSLVKGKVVIGAFRTIPPGYKPlePRQTTS 159

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 199 EYQTIPLNKIEDFGVHCKQYYPLEISYFKSALDRRLLDSLWNKYWVNTLGSSGLLTNT-EYTTGQIMDLSEKLEQSENFL 277
Cdd:cd08069 160 NIGHLPKPKIEDFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENSnEYTIKQILDLAEKLEKAEQQE 239

                       250       260
                ....*....|....*....|....*....
gi 17137694 278 GRGT-DVNEKRSEDKLSKAtRDCSRSTIE 305
Cdd:cd08069 240 ERLTgEELDIANVGKLDKA-RDSSKIHLE 267

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 17137694  41 PWEKDPHFFKDIKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVNAQAQAYEYMTAYmEA 120
Cdd:cd08069   1 PWKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGKVDDYTIIVVDVFALPVEGTETRVNAQDEFQEYMVQY-EM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 121 AKEVGRMEHAVGWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVVDPVRTVSAGKVCLGAFRTYPKGYKP--PNEEPS 198
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSLVKGKVVIGAFRTIPPGYKPlePRQTTS 159

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 199 EYQTIPLNKIEDFGVHCKQYYPLEISYFKSALDRRLLDSLWNKYWVNTLGSSGLLTNT-EYTTGQIMDLSEKLEQSENFL 277
Cdd:cd08069 160 NIGHLPKPKIEDFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENSnEYTIKQILDLAEKLEKAEQQE 239

                       250       260
                ....*....|....*....|....*....
gi 17137694 278 GRGT-DVNEKRSEDKLSKAtRDCSRSTIE 305
Cdd:cd08069 240 ERLTgEELDIANVGKLDKA-RDSSKIHLE 267

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 17137694     52 IKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVnaQAQAYEYMTAYMEAAKEVGRMEHAV 131
Cdd:smart00232   2 VKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKDRPEVKEVFAVPNEPQDDSV--QEYDEDYSHLMDEELKKVNKDLEIV 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 17137694    132 GWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVVDPVRTVSaGKVCLGAFRTYPK 188
Cdd:smart00232  80 GWYHSHPDESPFPSEVDVATHESYQAPWPISVVLIVDPIKSFQ-GRLSLRAFRLTPE 135

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 17137694  41 PWEKDPHFFKDIKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVNAQAQAYEYMTAYmEA 120
Cdd:cd08069   1 PWKPDPDYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGKVDDYTIIVVDVFALPVEGTETRVNAQDEFQEYMVQY-EM 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 121 AKEVGRMEHAVGWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVVDPVRTVSAGKVCLGAFRTYPKGYKP--PNEEPS 198
Cdd:cd08069  80 LKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSLVKGKVVIGAFRTIPPGYKPlePRQTTS 159

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694 199 EYQTIPLNKIEDFGVHCKQYYPLEISYFKSALDRRLLDSLWNKYWVNTLGSSGLLTNT-EYTTGQIMDLSEKLEQSENFL 277
Cdd:cd08069 160 NIGHLPKPKIEDFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENSnEYTIKQILDLAEKLEKAEQQE 239

                       250       260
                ....*....|....*....|....*....
gi 17137694 278 GRGT-DVNEKRSEDKLSKAtRDCSRSTIE 305
Cdd:cd08069 240 ERLTgEELDIANVGKLDKA-RDSSKIHLE 267

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 17137694     52 IKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVnaQAQAYEYMTAYMEAAKEVGRMEHAV 131
Cdd:smart00232   2 VKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKDRPEVKEVFAVPNEPQDDSV--QEYDEDYSHLMDEELKKVNKDLEIV 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 17137694    132 GWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVVDPVRTVSaGKVCLGAFRTYPK 188
Cdd:smart00232  80 GWYHSHPDESPFPSEVDVATHESYQAPWPISVVLIVDPIKSFQ-GRLSLRAFRLTPE 135

Cop9 signalosome subunit 5 C-terminal domain; The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN), a large multiprotein complex that resembles the 19S lid of the 26S proteasome, plays a central role in the regulation of the E3-cullin RING ubiquitin ligases (CRLs). The catalytic activity of the CSN complex is carried by subunit 5 (CSN5), also known as c-Jun activation domain-binding protein-1 (Jab1). This entry is the C-terminal domain found in CSN5 proteins. CSN5, whose two C-terminal helices form an antiparallel hairpin, inserts its final C-terminal helix (helix II) into the central CSN6 framework at the core of the bundle. Deletion of the C-terminal helices has a pronounced effect on CSN integrity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694   249 SSGLLTNTEYTTGQIMDLSEKLEQSENFLGRG-------TDVNEKRSEDKLSKATRDCSRSTIELIHGLMAQIVKDKLFN 321
Cdd:pfam18323   2 QSPLLTNRDYGTKQILDLAEKLEQAESSVSRSgagggglGGGGKKKEDSQLEKVVKDSNKIAIEEVHGLMAQVVKDKLFN 81

Mov34/MPN/PAD-1 family: BRCC36, a subunit of BRCA1-A complex; BRCC36 (BRCA1-A complex subunit BRCC36; BRCA1/BRCA2-containing complex subunit 36; BRCA1/BRCA2-containing complex subunit 3; BRCC3; BRISC complex subunit BRCC36; BRCC36 isopeptidase complex; Lys-63-specific deubiquitinase BRCC36) and BRCC36-like domains are members of JAMM/MPN+ deubiquitinases (DUBs), possibly with Zn2+-dependent ubiquitin isopeptidase activity. BRCC36 is part of the BRCA1/BRCA2/BARD1-containing nuclear complex that displays an E3 ubiquitin ligase activity. It is targeted to DNA damage foci after irradiation; RAP80 recruits the Abraxas-BRCC36-BRCA1-BARD1 complex to DNA double strand breaks (DSBs) for DNA repair through specific recognition of Lys 63-linked polyubiquitinated proteins by its tandem ubiquitin-interacting motifs. A new protein, MERIT40 (mediator of RAP80 interactions and targeting 40 kDa), also named NBA1 (new component of the BRCA1 A complex), exists in the same BRCA1-containing complex and is essential for the integrity of the complex. There are studies suggesting that MERIT40/NBA1 ties BRCA1 complex integrity, DSB recognition, and ubiquitin chain activities to the DNA damage response. It has also been shown that BRCA1-containing complex resembles the lid complex of the 26S proteasome.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694  50 KDIKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFA-------LP--------VE-GTETRVNAQAQAyEY 113
Cdd:cd08068   2 SKVHLSADVYLVCLTHALSTEKEEVMGLLIGEIEVSKKGEEVAIVhisaviiLRrsdkrkdrVEiSPEQLSAASTEA-ER 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 17137694 114 MTaymeaaKEVGRMEHAVGWYHSHPGYGCWLSGIDVSTQMLNQTYQEPFVAIVV 167
Cdd:cd08068  81 LT------EETGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDSGFVGLIF 128

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 17137694  52 IKISALALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMdafALPVEgtetrvNAQAQAY--------EYMTAYMEAAKe 123
Cdd:COG1310   2 LVLPRELLDAILAHAEAAYPEECCGLLLGKGGGDKRVTR---VYPAR------NVAESPEtrfeidpeDLLAAEREARE- 71

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 17137694 124 vgRMEHAVGWYHSHPGYGCWLSGIDvstqmLNQTYQEPFVAIVVDpvrtVSAGKVCLGAFR 184
Cdd:COG1310  72 --RGLEIVGIYHSHPDGPAYPSETD-----RAQAAWPGLPYLIVS----LPDGGPELRAWR 121

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 17137694  59 LLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALPVEGTETRVNAqaqayEYMTAYMEAAKEVGrmEHAVGWYHSHP 138
Cdd:cd07767   1 LKMFLDAAKSINGKEVIGLLYGSKTKKVLDVDEVIAVPFDEGDKDDNV-----WFLMYLDFKKLNAG--LRIVGWYHTHP 73

                        90       100       110
                ....*....|....*....|....*....|.
gi 17137694 139 GYGCWLSGIDVSTQMLNQTYQEPFVAIVVDP 169
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 17137694  58 ALLKMVMHARSGGTLEVMGLMLGKVEDNTMIVMDAFALP--VEGTETR--VNAQaqayEYMTAYMEAAKevgRMEHAVGW 133
Cdd:cd08070   3 LLEAILAHAEAEYPEECCGLLLGKGGGVTAIVTEVYPVRnvAESPRRRfeIDPA----EQLAAQREARE---RGLEVVGI 75

                        90
                ....*....|....*.
gi 17137694 134 YHSHPGYGCWLSGIDV 149
Cdd:cd08070  76 YHSHPDGPARPSETDL 91

Prokaryotic homologs of the JAB domain; These are metalloenzymes that function as the ubiquitin isopeptidase/ deubiquitinase in the ubiquitin-based signaling and protein turnover pathways in eukaryotes. Prokaryotic JAB domains are predicted to have a similar role in their cognates of the ubiquitin modification pathway. The domain is widely found in bacteria, archaea and phages where they are present in several gene contexts in addition to those that correspond to the prokaryotic cognates of the eukaryotic Ub pathway. Other contexts in which JAB domains are present include gene neighbor associations with ubiquitin fold domains in cysteine and siderophore biosynthesis, and phage tail morphogenesis, where they are shown or predicted to process the associated ubiquitin. A distinct family, the RadC-like JAB domains are widespread in bacteria and are predicted to function as nucleases. In halophilic archaea the JAB domain shows strong gene-neighborhood associations with a nucleotidyltransferase suggesting a role in nucleotide metabolism.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137694    58 ALLKMVMHARSGGTLEVMGLMLGKVEDN-TMIVMDAFALPVEGTETRVNAQAQAYEYMTAymeaakevgRMEHAVGWYHS 136
Cdd:pfam14464   4 LLDAIVAHARAAHPLECCGILLGNELESqSVRVIPLVNPMRNRFEIDPGDSLRRVKAARE---------RGLELVGIYHS 74

                  ...
gi 17137694   137 HPG 139
Cdd:pfam14464  75 HPG 77