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 2781188343  28 DNGETVHISALALLKMLKHGRAGVPMEVMGLMLGEfVDDYTISCVDVFAMPQSGTTVTVESVDhVFQTKMLD--MLKQTG 105
Cdd:cd08069     7 DYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQTG 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 106 RPEMVVGWYHSHPGFGCWLSSVDVNTQQSFEQLHPRAVAVVIDPIQS-VRGKVVIDAFRSINPAalATGQESRQTTSNIG 184
Cdd:cd08069    85 RPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPG--YKPLEPRQTTSNIG 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 185 HLNKPSIQaLIHGLNRHYYSLAIDYKKTEAEQGMLLNLHKRGWTEGLKMKDFEEMEqgSQKAIENMLNLAVAYTKSVQEE 264
Cdd:cd08069   163 HLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQE 239

                         250       260       270
                  ....*....|....*....|....*....|..
gi 2781188343 265 STMTEEQLKTRHVGKLDpkrHLSEAAEKAMED 296
Cdd:cd08069   240 ERLTGEELDIANVGKLD---KARDSSKIHLEE 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 2781188343  28 DNGETVHISALALLKMLKHGRAGVPMEVMGLMLGEfVDDYTISCVDVFAMPQSGTTVTVESVDhVFQTKMLD--MLKQTG 105
Cdd:cd08069     7 DYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQTG 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 106 RPEMVVGWYHSHPGFGCWLSSVDVNTQQSFEQLHPRAVAVVIDPIQS-VRGKVVIDAFRSINPAalATGQESRQTTSNIG 184
Cdd:cd08069    85 RPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPG--YKPLEPRQTTSNIG 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 185 HLNKPSIQaLIHGLNRHYYSLAIDYKKTEAEQGMLLNLHKRGWTEGLKMKDFEEMEqgSQKAIENMLNLAVAYTKSVQEE 264
Cdd:cd08069   163 HLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQE 239

                         250       260       270
                  ....*....|....*....|....*....|..
gi 2781188343 265 STMTEEQLKTRHVGKLDpkrHLSEAAEKAMED 296
Cdd:cd08069   240 ERLTGEELDIANVGKLD---KARDSSKIHLEE 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 2781188343  28 DNGETVHISALALLKMLKHGRAGVPM--EVMGLMLGEFVDDYTISCVDVFAMPQSGTTVTVESV--DHVFQTKMLDMLKQ 103
Cdd:pfam01398   1 SSVRTVIIHPLVLLKILDHANRGGKIgeEVMGVLLGKLEGDGTIEITNSFALPQEETEDDVNAValDQEYMENMHEMLKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2781188343 104 TGRPEMVVGWYHSHPGFgCWLSSVDVNTQQSFEQLHPR 141
Cdd:pfam01398  81 VNRKEEVVGWYHTHPGL-CWLSSVDVHTHALYQRMIPE 117

26S proteasome regulatory subunit; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343  31 ETVHISALALLKMLKHGR---AGVPMEVMGLMLGEFVDDyTISCVDVFAMP--QSGTTVTVESVDHVFQTKMLDMLKQTG 105
Cdd:PLN03246    6 EKVVVHPLVLLSIVDHYNrvaKDTRKRVVGVLLGSSFRG-RVDVTNSFAVPfeEDDKDPSIWFLDHNYLESMFGMFKRIN 84

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2781188343 106 RPEMVVGWYHSHPGfgcwLSSVDVNTQQSFEQLHPRAVAVVIDpIQSVRGKVVIDAFRSINPAALATGQESRQT 179
Cdd:PLN03246   85 AKEHVVGWYSTGPK----LRENDLDIHELFNDYVPNPVLVIID-VQPKELGIPTKAYYAVEEVKENATQKSQKV 153

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 2781188343  28 DNGETVHISALALLKMLKHGRAGVPMEVMGLMLGEfVDDYTISCVDVFAMPQSGTTVTVESVDhVFQTKMLD--MLKQTG 105
Cdd:cd08069     7 DYFEKVYISSLALLKMLKHARAGGPIEVMGLMLGK-VDDYTIIVVDVFALPVEGTETRVNAQD-EFQEYMVQyeMLKQTG 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 106 RPEMVVGWYHSHPGFGCWLSSVDVNTQQSFEQLHPRAVAVVIDPIQS-VRGKVVIDAFRSINPAalATGQESRQTTSNIG 184
Cdd:cd08069    85 RPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAVVVDPIRSlVKGKVVIGAFRTIPPG--YKPLEPRQTTSNIG 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 185 HLNKPSIQaLIHGLNRHYYSLAIDYKKTEAEQGMLLNLHKRGWTEGLKMKDFEEMEqgSQKAIENMLNLAVAYTKSVQEE 264
Cdd:cd08069   163 HLPKPKIE-DFGGHNKQYYSLPIEYFKSSLDRKLLLNLWNKYWVNTLSLSPLLENS--NEYTIKQILDLAEKLEKAEQQE 239

                         250       260       270
                  ....*....|....*....|....*....|..
gi 2781188343 265 STMTEEQLKTRHVGKLDpkrHLSEAAEKAMED 296
Cdd:cd08069   240 ERLTGEELDIANVGKLD---KARDSSKIHLEE 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 2781188343   32 TVHISALALLKMLKHGRAGVPMEVMGLMLGEFVDDyTISCVDVFAMPQSGTTVTVESVDHVFQTKMLDMLKQTGRPEMVV 111
Cdd:smart00232   1 EVKVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKD-RPEVKEVFAVPNEPQDDSVQEYDEDYSHLMDEELKKVNKDLEIV 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2781188343  112 GWYHSHPGFGCWLSSVDVNTQQSFEQLHPRAVAVVIDPIQSVRGKVVIDAFRSIN 166
Cdd:smart00232  80 GWYHSHPDESPFPSEVDVATHESYQAPWPISVVLIVDPIKSFQGRLSLRAFRLTP 134

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 2781188343  31 ETVHISALALLKMLKHGRAGVPMEVMGLMLGeFVDDYTISCVDVFAMPQSGT--TVTVESVDHVFQTKMLDMLKQTGRPE 108
Cdd:cd08065     1 TSVQIDGLVVLKIIKHCKEELPELVQGQLLG-LDVGGTLEVTNCFPFPKSEEddSDRADEDIADYQLEMMRLLREVNVDH 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 109 MVVGWYHSHPgFGCWLSSVDVNTQQSFEQLHPRAVAVVIDPIQSVRGKVVIDAFRsINPAALATGQESRQTT-----SNI 183
Cdd:cd08065    80 NHVGWYQSTY-LGSFFTRDLIETQYNYQEAIEESVVLVYDPSKTSQGSLSLKAYR-LSEKFMELYKEGKFSTeslreANL 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343 184 GH-----------LNKPSIQALIHGLNRHYYSLAIDYkkteaeqgMLLNL-HKRGWTEGLK--MKDFEEMEQGSQKAIen 249
Cdd:cd08065   158 TFsnifeeipvviRNSHLVNALLSELEEDSPSSQSDF--------DRLDLsTNSFLEKNLEllMESVDELSQEQGKFN-- 227

                         250       260
                  ....*....|....*....|....*.
gi 2781188343 250 mlnlavAYTKSVQEESTMTEEQLKTR 275
Cdd:cd08065   228 ------YYQRNLARQQAQIQQWLQKR 247

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 2781188343  40 LLKMLKHGRAGVPMEVMGLMLGEFVDD-YTISCVdvFAMPQSGTTVTVESVdhvfqTKMLDMLKQTGRPEMVVGWYHSHP 118
Cdd:cd07767     1 LKMFLDAAKSINGKEVIGLLYGSKTKKvLDVDEV--IAVPFDEGDKDDNVW-----FLMYLDFKKLNAGLRIVGWYHTHP 73

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2781188343 119 GFGCWLSSVDVNTQQSFEQLHPRAVAVVIDP 149
Cdd:cd07767    74 KPSCFLSPNDLATHELFQRYFPEKVMIIVDV 104

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2781188343  32 TVHISALALLKMLKHGRA----GVpmEVMGLMLGEFVDD-YTIScvDVFAMPQSGTTVTVESVDHV----FQTKMlDMLk 102
Cdd:cd08066     3 QVVVPADLMDKFLQLAEPntsrNL--ETCGILCGKLSNNaFFIT--HLIIPKQSGTSDSCQTTNEEelfdFQDQH-DLI- 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 2781188343 103 qtgrpemVVGWYHSHPGFGCWLSSVDVNTQQSFEQLHPRAVAVVIDP 149
Cdd:cd08066    77 -------TLGWIHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAP 116

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 2781188343  32 TVHISALALLKMLKHgrAGVPM-EVMGLMLGEF-VDDYTISCVDVFAMPQSGTTVTVESvDHVFQTKMLDMLKQTGrpEM 109
Cdd:cd08067     6 KVTVSSNALLLMDFH--CHLTTsEVIGYLGGTWdPNTQNLTILQAFPCRSRLTGLDCEM-DPVSETEIRESLESRG--LS 80

                          90       100
                  ....*....|....*....|....*....
gi 2781188343 110 VVGWYHSHPGFGCWLSSVDVNTQQSFEQL 138
Cdd:cd08067    81 VVGWYHSHPTFPPNPSLRDIDTQLDYQIM 109

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 2781188343  39 ALLKMLKHGRAGVPMEVMGLMLGEfVDDYTISCVDVFAMPQsgttvTVESVDHVF------QTKMLDMLKQTGRPemVVG 112
Cdd:cd08070     3 LLEAILAHAEAEYPEECCGLLLGK-GGGVTAIVTEVYPVRN-----VAESPRRRFeidpaeQLAAQREARERGLE--VVG 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2781188343 113 WYHSHPGFGCWLSSVDVntqqsfEQLHPRAVAVVidpIQSVRGKV-VIDAFR 163
Cdd:cd08070    75 IYHSHPDGPARPSETDL------RLAWPPGVSYL---IVSLAGGApELRAWR 117

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 2781188343  43 MLKHGRAGVPMEVMGLMLGEfVDDytiSCVDVFAMPQSgtTVTVESVDHvfqtkmLDMLKQTGRpemVVGWYHSHPGFGC 122
Cdd:cd08059     6 ILVHAKDAHPDEFCGFLSGS-KDN---VMDELIFLPFV--SGSVSAVID------LAALEIGMK---VVGLVHSHPSGSC 70

                  ....*.
gi 2781188343 123 WLSSVD 128
Cdd:cd08059    71 RPSEAD 76