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 1953105454  36 TVAEKVDTVRIVHIHSVIILRRSDKRKDRVEISPEQLSAASTEAERLAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQA 115
Cdd:cd08068    35 EVSKKGEEVAIVHISAVIILRRSDKRKDRVEISPEQLSAASTEAERLTEETGRPMRVVGWYHSHPHITVWPSHVDVRTQA 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953105454 116 MYQMMDQGFVGLIFSCFIEDKNTKTGRVLYTCFQSIQAQKssesphgprdfwsSSQHISIEgqkeeeryerieIPIHIVP 195
Cdd:cd08068   115 MYQMMDSGFVGLIFSCFNEDKSTKMGEVQVTCFQSVQGNK-------------AGQYERIE------------VPLEIVP 169

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953105454 196 HVTIGKVCLESAVELPKILCQEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLE 267
Cdd:cd08068   170 TSTISEACLESLVELPEILYQEEEDAYNKALQSCDLDPLTKIHNGSVYTKSLCHILETISGPLLQLLEARLE 241

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 1953105454  36 TVAEKVDTVRIVHIHSVIILRRSDKRKDRVEISPEQLSAASTEAERLAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQA 115
Cdd:cd08068    35 EVSKKGEEVAIVHISAVIILRRSDKRKDRVEISPEQLSAASTEAERLTEETGRPMRVVGWYHSHPHITVWPSHVDVRTQA 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953105454 116 MYQMMDQGFVGLIFSCFIEDKNTKTGRVLYTCFQSIQAQKssesphgprdfwsSSQHISIEgqkeeeryerieIPIHIVP 195
Cdd:cd08068   115 MYQMMDSGFVGLIFSCFNEDKSTKMGEVQVTCFQSVQGNK-------------AGQYERIE------------VPLEIVP 169

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953105454 196 HVTIGKVCLESAVELPKILCQEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLE 267
Cdd:cd08068   170 TSTISEACLESLVELPEILYQEEEDAYNKALQSCDLDPLTKIHNGSVYTKSLCHILETISGPLLQLLEARLE 241

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 1953105454   45 RIVHIHSVIILRRsDKRKDRVEISPEQLSAASTEAERLaelTGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDQGF 124
Cdd:smart00232  35 DRPEVKEVFAVPN-EPQDDSVQEYDEDYSHLMDEELKK---VNKDLEIVGWYHSHPDESPFPSEVDVATHESYQAPWPIS 110

                           90       100
                   ....*....|....*....|....*....
gi 1953105454  125 VGLIfscfIEDKNTKTGRVLYTCFQSIQA 153
Cdd:smart00232 111 VVLI----VDPIKSFQGRLSLRAFRLTPE 135

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 1953105454  36 TVAEKVDTVRIVHIHSVIILRRSDKRKDRVEISPEQLSAASTEAERLAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQA 115
Cdd:cd08068    35 EVSKKGEEVAIVHISAVIILRRSDKRKDRVEISPEQLSAASTEAERLTEETGRPMRVVGWYHSHPHITVWPSHVDVRTQA 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953105454 116 MYQMMDQGFVGLIFSCFIEDKNTKTGRVLYTCFQSIQAQKssesphgprdfwsSSQHISIEgqkeeeryerieIPIHIVP 195
Cdd:cd08068   115 MYQMMDSGFVGLIFSCFNEDKSTKMGEVQVTCFQSVQGNK-------------AGQYERIE------------VPLEIVP 169

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953105454 196 HVTIGKVCLESAVELPKILCQEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLE 267
Cdd:cd08068   170 TSTISEACLESLVELPEILYQEEEDAYNKALQSCDLDPLTKIHNGSVYTKSLCHILETISGPLLQLLEARLE 241

BRCC36 C-terminal helical domain; This is the C-terminal domain of BRCC36, a Zn2+ dependent deubiquitinating enzyme, present in Camponotus floridanus. BRCC36 hydrolyzes lysine linked ubiquitin chains as part of macromolecular complexes that participate in either interferon signalling or DNA-damage recognition. The domain consists of 2 non canonical helices. The domain interacts hydrophobically with helices alpha 4 and alpha 5 of KIAA0157 in the form of a coiled coil helical bundle. This interaction helps establish the association of BRCC36 with KIAA0157, a pseudo-DUB MPN- protein that is essential for the activity of BRCC36.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953105454 203 CLESAVELPKILCQEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLEQNQQHLQELQQEKEE 282
Cdd:pfam18110   1 CLESLTELPEILFQEEKEAYEKAKKSGSLDLLTKIHNGSVFTKSLCHITEAISGPLLQALEARLKLNKNRLAALKQEKEE 80

                  .
gi 1953105454 283 L 283
Cdd:pfam18110  81 L 81

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1953105454  47 VHIHSVIILRRSDKRKDRVEISPEQLSAasTEAERLAELTGRPMRVVGWYHSHPHItVWPSHVDVRTQAMYQMMDQG 123
Cdd:pfam01398  44 IEITNSFALPQEETEDDVNAVALDQEYM--ENMHEMLKKVNRKEEVVGWYHTHPGL-CWLSSVDVHTHALYQRMIPE 117

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
                  ....*....|....*....|....*....|....*....|....*.
gi 1953105454  82 LAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDQGFVGL 127
Cdd:cd08069    79 MLKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAV 124

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 1953105454  47 VHIHSVIILR-RSDKRKDRVEISPEQLsaasTEAERLAELTGrpMRVVGWYHSHPHITVWPSHVDVRtqamyQMMDQGFV 125
Cdd:cd08070    32 AIVTEVYPVRnVAESPRRRFEIDPAEQ----LAAQREARERG--LEVVGIYHSHPDGPARPSETDLR-----LAWPPGVS 100

                  ....*
gi 1953105454 126 GLIFS 130
Cdd:cd08070   101 YLIVS 105

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1953105454  59 DKRKDRVEISPEQLSAASTEAERLAELTGrpMRVVGWYHSHPHITVWPSHVDVRTQ 114
Cdd:cd08059    27 DNVMDELIFLPFVSGSVSAVIDLAALEIG--MKVVGLVHSHPSGSCRPSEADLSLF 80