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 146134497 252 KFQPFNVAVSSNVLFLLDFHCHLTRSEVVGYLGGRWDINNQMLTVLRAFPCRSRL--GDTDTAATVEEEIYQVLFLRGLS 329
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134497 330 LVGWYHSHPHSPAVPSLQDIDAQMEYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKICPFWVMPPPEQRPSDYGIPMD 409
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 146134497 410 VEMAYVQDSFLTNDVLQEMVMLAEFYK 436
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 146134497 252 KFQPFNVAVSSNVLFLLDFHCHLTRSEVVGYLGGRWDINNQMLTVLRAFPCRSRL--GDTDTAATVEEEIYQVLFLRGLS 329
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134497 330 LVGWYHSHPHSPAVPSLQDIDAQMEYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKICPFWVMPPPEQRPSDYGIPMD 409
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 146134497 410 VEMAYVQDSFLTNDVLQEMVMLAEFYK 436
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 146134497 278 EVVGYLGGRWDINNqmlTVLRAFPCRSRLGDTDTAATVE-EEIYQVLFL---RGLSLVGWYHSHPHSPAVPSLQDIdAQM 353
Cdd:COG1310   23 ECCGLLLGKGGGDK---RVTRVYPARNVAESPETRFEIDpEDLLAAEREareRGLEIVGIYHSHPDGPAYPSETDR-AQA 98

                 ..
gi 146134497 354 EY 355
Cdd:COG1310   99 AW 100

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 146134497  257 NVAVSSNVLflLDFHCHLTRS-----EVVGYLGGRWDiNNQMLTVLRAFPCRSRLGDTDTAATVEEEIYQV----LFL-- 325
Cdd:pfam01398   5 TVIIHPLVL--LKILDHANRGgkigeEVMGVLLGKLE-GDGTIEITNSFALPQEETEDDVNAVALDQEYMEnmheMLKkv 81

                          90       100       110
                  ....*....|....*....|....*....|..
gi 146134497  326 -RGLSLVGWYHSHPHsPAVPSLQDIDAQMEYQ 356
Cdd:pfam01398  82 nRKEEVVGWYHTHPG-LCWLSSVDVHTHALYQ 112

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 146134497 252 KFQPFNVAVSSNVLFLLDFHCHLTRSEVVGYLGGRWDINNQMLTVLRAFPCRSRL--GDTDTAATVEEEIYQVLFLRGLS 329
Cdd:cd08067    1 KIQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLtgLDCEMDPVSETEIRESLESRGLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 146134497 330 LVGWYHSHPHSPAVPSLQDIDAQMEYQLRLQGSSNGFQPCLALLCSPYYSGNPGPESKICPFWVMPPPEQRPSDYGIPMD 409
Cdd:cd08067   81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSDSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENRPNEYGVPML 160

                        170       180
                 ....*....|....*....|....*..
gi 146134497 410 VEMAYVQDSFLTNDVLQEMVMLAEFYK 436
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 146134497 265 LFLLDFHCHL-TRSEVVGYLGGRWDINNQMLTVLR---AFPCRSRlgdtdTAATVEEEIYQVLFLRGLSLVGWYHSHPHS 340
Cdd:cd08058    3 LLKMLQHAESnTGIEVMGLLCGELTHNEFTDKHVIvpkQSAGPDS-----CTGENVEELFNVQTGRPLLVVGWYHSHPTF 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 146134497 341 PAVPSLQDIDAQMEYQLRLQGSsngfqpcLALLCSPYYSGNPGPESKI 388
Cdd:cd08058   78 TAWLSSVDIHTQASYQLMLPEA-------IAIVVSPKHRNKDTGIFRL 118

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 146134497 278 EVVGYLGGRwdINNQMLTVLRAFPCRSRLGDTDTAATVE-EEIYQVL-FLR--GLSLVGWYHSHPHSPAVPSLQDIdAQM 353
Cdd:cd08070   18 ECCGLLLGK--GGGVTAIVTEVYPVRNVAESPRRRFEIDpAEQLAAQrEARerGLEVVGIYHSHPDGPARPSETDL-RLA 94

                 ..
gi 146134497 354 EY 355
Cdd:cd08070   95 WP 96

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 146134497  257 NVAVSSNVLflLDFHCHLTRS-----EVVGYLGGRWDiNNQMLTVLRAFPCRSRLGDTDTAATVEEEIYQV----LFL-- 325
Cdd:pfam01398   5 TVIIHPLVL--LKILDHANRGgkigeEVMGVLLGKLE-GDGTIEITNSFALPQEETEDDVNAVALDQEYMEnmheMLKkv 81

                          90       100       110
                  ....*....|....*....|....*....|..
gi 146134497  326 -RGLSLVGWYHSHPHsPAVPSLQDIDAQMEYQ 356
Cdd:pfam01398  82 nRKEEVVGWYHTHPG-LCWLSSVDVHTHALYQ 112

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 146134497  278 EVVGYLGGRWDINNQMLTVLRAFPCRSRLGD--TDTAATVEEeiyqvLFLRGLSLVGWYHSHPHSPAVPSLQDID 350
Cdd:pfam14464  19 ECCGILLGNELESQSVRVIPLVNPMRNRFEIdpGDSLRRVKA-----ARERGLELVGIYHSHPGGPAYPSETDRR 88

Mov34/MPN/PAD-1 family; AMSH (associated molecule with the Src homology 3 domain (SH3) of STAM (signal-transducing adapter molecule, also known as STAMBP)) and AMSH-like proteins (AMSH-LP) are members of JAMM/MPN+ deubiquitinases (DUBs), with Zn2+-dependent ubiquitin isopeptidase activity. 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. AMSH and AMSH-LP are anchored on the early endosomal membrane via interaction with the clathrin coat. AMSH shares a common SH3-binding site with another endosomal DUB, UBPY (ubiquitin-specific protease Y; also known as USP8), the latter being a cysteine protease that does not discriminate between Lys48 and Lys63-linked ubiquitin. AMSH is involved in the degradation of EGF receptor (EGFR) and possibly other ubiquitinated endocytosed proteins. AMSH also interacts with CHMP1, CHMP2, and CHMP3 proteins, all of which are components of ESCRT-III, suggested to be required for EGFR down-regulation. The function of AMSH-LP has not been elucidated; however, it exhibits two fundamentally distinct features from AMSH: first, there is a substitution in the critical amino acid residue in the SH3-binding motif (SBM) in the human AMSH-LP, but not in its mouse ortholog, and lacks STAM-binding ability; second, AMSH-LP lacks the ability to interact with CHMP proteins. It is therefore likely that AMSH and AMSH-LP play different roles on early endosomes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 146134497 307 GDTDTAATV-EEEIYQVLFLRGLSLVGWYHSHPHSPAVPSLQDIDAQMEYQLRLQGSsngfqpcLALLCSPYY 378
Cdd:cd08066   53 GTSDSCQTTnEEELFDFQDQHDLITLGWIHTHPTQTCFLSSVDLHTHCSYQLMLPEA-------IAIVCAPKY 118

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 146134497 326 RGLSLVGWYHSHPHSPAVPSLQDIDAQMEYQlRLQgssngfQPCLALLCSPYYSGNPGpesKIC--------PFWVMPPP 397
Cdd:cd08069   85 RPENVVGWYHSHPGYGCWLSGIDVNTQQLNQ-QLQ------DPFVAVVVDPIRSLVKG---KVVigafrtipPGYKPLEP 154

                 ....*....
gi 146134497 398 EQRPSDYGI 406
Cdd:cd08069  155 RQTTSNIGH 163