Mov34/MPN/PAD-1 family: Histone H2A deubiquitinase; This family includes histone H2A deubiquitinase (Histone H2A DUB;MYSM1; myb-like, SWIRM and MPN domains 1; 2ADUB; 2A-DUB; KIAA19152ADUB, or KIAA1915/MYSM1), a member of JAMM/MPN+ deubiquitinases (DUBs), with possible Zn2+-dependent ubiquitin isopeptidase activity. It contains the SWIRM (Swi3p, Rsc8p and Moira), and SANT (SWI-SNF, ADA N-CoR, TFIIIB)/Myb domains; the SANT, but not the SWIRM, domain can bind directly to DNA. 2A-DUB is specific for monoubiquitinated H2A (uH2A), regulating transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes. 2A-DUB interacts with p/CAF (p300/CBP-associated factor) in a co-regulatory protein complex, where the status of acetylation of nucleosomal histones modulates its deubiquitinase activity. 2A-DUB is a positive regulator of androgen receptor (AR) transactivation activity on a reporter gene; it participates in transcriptional regulation events in androgen receptor-dependent gene activation. In prostate tumors, the levels of uH2A are dramatically decreased, thus 2A-DUB serving as a cancer-related marker.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 266 KFQPFNVAVSSNVLFLLDFHSHLTRSEVVGYLGGRWDVNSQMLTVLRAFPCRSRL--GDAETAAAIEEEIYQSLFLRGLS 343
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 344 LVGWYHSHPHSPALPSLQDIDAQMDYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKISPFWVMPPPEQRPSDYGIPMD 423
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 664805955 424 VEMAYVQDSFLTNDILHEMMLLVEFYK 450
Cdd:cd08067  161 MSYTVSQDEFLTQDVLKELRWLVEFYR 187

Mov34/MPN/PAD-1 family: Histone H2A deubiquitinase; This family includes histone H2A deubiquitinase (Histone H2A DUB;MYSM1; myb-like, SWIRM and MPN domains 1; 2ADUB; 2A-DUB; KIAA19152ADUB, or KIAA1915/MYSM1), a member of JAMM/MPN+ deubiquitinases (DUBs), with possible Zn2+-dependent ubiquitin isopeptidase activity. It contains the SWIRM (Swi3p, Rsc8p and Moira), and SANT (SWI-SNF, ADA N-CoR, TFIIIB)/Myb domains; the SANT, but not the SWIRM, domain can bind directly to DNA. 2A-DUB is specific for monoubiquitinated H2A (uH2A), regulating transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes. 2A-DUB interacts with p/CAF (p300/CBP-associated factor) in a co-regulatory protein complex, where the status of acetylation of nucleosomal histones modulates its deubiquitinase activity. 2A-DUB is a positive regulator of androgen receptor (AR) transactivation activity on a reporter gene; it participates in transcriptional regulation events in androgen receptor-dependent gene activation. In prostate tumors, the levels of uH2A are dramatically decreased, thus 2A-DUB serving as a cancer-related marker.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 266 KFQPFNVAVSSNVLFLLDFHSHLTRSEVVGYLGGRWDVNSQMLTVLRAFPCRSRL--GDAETAAAIEEEIYQSLFLRGLS 343
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 344 LVGWYHSHPHSPALPSLQDIDAQMDYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKISPFWVMPPPEQRPSDYGIPMD 423
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 664805955 424 VEMAYVQDSFLTNDILHEMMLLVEFYK 450
Cdd:cd08067  161 MSYTVSQDEFLTQDVLKELRWLVEFYR 187

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 664805955 292 EVVGYLGGRWDVNSqmlTVLRAFPCRSRLGDAETAAAIEEEIYQSLFL----RGLSLVGWYHSHPHSPALPSLQDIdAQM 367
Cdd:COG1310   23 ECCGLLLGKGGGDK---RVTRVYPARNVAESPETRFEIDPEDLLAAEReareRGLEIVGIYHSHPDGPAYPSETDR-AQA 98

                 ..
gi 664805955 368 DY 369
Cdd:COG1310   99 AW 100

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 664805955  281 LLDFHSHLTRS---EVVGYLGGRWDVNSQMLTVLRAFPCRSRlgdAETAAAIEEEIYQSLFLRGLSLVGWYHSHPHSPAL 357
Cdd:pfam14464   5 LDAIVAHARAAhplECCGILLGNELESQSVRVIPLVNPMRNR---FEIDPGDSLRRVKAARERGLELVGIYHSHPGGPAY 81

                  ....*..
gi 664805955  358 PSLQDID 364
Cdd:pfam14464  82 PSETDRR 88

Mov34/MPN/PAD-1 family: Histone H2A deubiquitinase; This family includes histone H2A deubiquitinase (Histone H2A DUB;MYSM1; myb-like, SWIRM and MPN domains 1; 2ADUB; 2A-DUB; KIAA19152ADUB, or KIAA1915/MYSM1), a member of JAMM/MPN+ deubiquitinases (DUBs), with possible Zn2+-dependent ubiquitin isopeptidase activity. It contains the SWIRM (Swi3p, Rsc8p and Moira), and SANT (SWI-SNF, ADA N-CoR, TFIIIB)/Myb domains; the SANT, but not the SWIRM, domain can bind directly to DNA. 2A-DUB is specific for monoubiquitinated H2A (uH2A), regulating transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes. 2A-DUB interacts with p/CAF (p300/CBP-associated factor) in a co-regulatory protein complex, where the status of acetylation of nucleosomal histones modulates its deubiquitinase activity. 2A-DUB is a positive regulator of androgen receptor (AR) transactivation activity on a reporter gene; it participates in transcriptional regulation events in androgen receptor-dependent gene activation. In prostate tumors, the levels of uH2A are dramatically decreased, thus 2A-DUB serving as a cancer-related marker.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 266 KFQPFNVAVSSNVLFLLDFHSHLTRSEVVGYLGGRWDVNSQMLTVLRAFPCRSRL--GDAETAAAIEEEIYQSLFLRGLS 343
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 344 LVGWYHSHPHSPALPSLQDIDAQMDYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKISPFWVMPPPEQRPSDYGIPMD 423
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 664805955 424 VEMAYVQDSFLTNDILHEMMLLVEFYK 450
Cdd:cd08067  161 MSYTVSQDEFLTQDVLKELRWLVEFYR 187

Mpr1p, Pad1p N-terminal (MPN) domains with catalytic isopeptidase activity (metal-binding); eukaryotic; This family contains eukaryotic MPN (also known as Mov34, PAD-1, JAMM, JAB, MPN+) domains found in proteins with a variety of functions, including AMSH (associated molecule with the Src homology 3 domain (SH3) of STAM), H2A-DUB (histone H2A deubiquitinase), BRCC36 (BRCA1/BRCA2-containing complex subunit 36), as well as Rpn11 (regulatory particle number 11) and CSN5 (COP9 signalosome complex subunit 5). 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. Rpn11 is responsible for substrate deubiquitination during proteasomal degradation. It is essential for maintaining a correct cell cycle and normal mitochondrial morphology and physiology. CSN5 is critical for nuclear export and the degradation of several tumor suppressor proteins, including p53, p27, and Smad4. Over-expression of CSN5 has been implicated in cancer initiation and progression. AMSH specifically cleaves Lys 63 and not Lys48-linked polyubiquitin (poly-Ub) chains, thus facilitating the recycling and subsequent trafficking of receptors to the cell surface. It is involved in the degradation of EGF receptor (EGFR) and possibly other ubiquitinated endocytosed proteins. 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. 2A-DUB is specific for monoubiquitinated H2A (uH2A), regulating transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes. It is a positive regulator of androgen receptor (AR) transactivation activity on a reporter gene and serves as a marker in prostate tumors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 664805955 279 LFLLDFHSHL-TRSEVVGYLGGRWDVNSQMLTVLR---AFPCRSrLGDAETAAAIEEEIYQslflRGLSLVGWYHSHPHS 354
Cdd:cd08058    3 LLKMLQHAESnTGIEVMGLLCGELTHNEFTDKHVIvpkQSAGPD-SCTGENVEELFNVQTG----RPLLVVGWYHSHPTF 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 664805955 355 PALPSLQDIDAQMDYQLRLQGSsngfqpcLALLCSPYYSGNPGPESKIS 403
Cdd:cd08058   78 TAWLSSVDIHTQASYQLMLPEA-------IAIVVSPKHRNKDTGIFRLT 119

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 664805955 292 EVVGYLGGRWDVNSqmLTVLRAFPCRSRLGDAETAAAIEEEIYQSLF----LRGLSLVGWYHSHPHSPALPSLQDI 363
Cdd:cd08070   18 ECCGLLLGKGGGVT--AIVTEVYPVRNVAESPRRRFEIDPAEQLAAQrearERGLEVVGIYHSHPDGPARPSETDL 91

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
                   ....*....|....*....|....*....|....*...
gi 664805955   340 RGLSLVGWYHSHPHSPALPSLQDIDAQMDYQLRLQGSS 377
Cdd:smart00232  74 KDLEIVGWYHSHPDESPFPSEVDVATHESYQAPWPISV 111

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 664805955 289 TRSEVVGYLGGRWDVNSQMLTVLRAFPCRSRLGDAETAAAIEEEIYQSLflRGLSLVGWYHSHPHSPALPSLQDIDAQMD 368
Cdd:cd07767   12 NGKEVIGLLYGSKTKKVLDVDEVIAVPFDEGDKDDNVWFLMYLDFKKLN--AGLRIVGWYHTHPKPSCFLSPNDLATHEL 89

                 ....*...
gi 664805955 369 YQLRLQGS 376
Cdd:cd07767   90 FQRYFPEK 97

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 664805955 340 RGLSLVGWYHSHPHSPALPSLQDIDAQMDYQlRLQgssngfQPCLALLCSPYYSGNPGpesK--------ISPFWVMPPP 411
Cdd:cd08069   85 RPENVVGWYHSHPGYGCWLSGIDVNTQQLNQ-QLQ------DPFVAVVVDPIRSLVKG---KvvigafrtIPPGYKPLEP 154

                 ....*....
gi 664805955 412 EQRPSDYGI 420
Cdd:cd08069  155 RQTTSNIGH 163