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 1927246371 548 QAPFQVIVCAETLLIMDMHAHVSRGEVIGLLGGMFNEEEKVLKICAAEPCNSVSTGLQCEMDPLSQTQACDVLSSLGFSV 627
Cdd:cd08067     2 IQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLTGLDCEMDPVSETEIRESLESRGLSV 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1927246371 628 VGWYHSHPSFHPNPSVRDIATQDQFQSYFS---RGGAPFIGMIVSPYDPANRSPHSQTTCLLVKESQEP-SGPQKLPYRF 703
Cdd:cd08067    82 VGWYHSHPTFPPNPSLRDIDTQLDYQIMFKgsdSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENrPNEYGVPMLM 161

                         170       180
                  ....*....|....*....|....*
gi 1927246371 704 DFLSSQDIPDWEQTLRRAQWIIHKY 728
Cdd:cd08067   162 SYTVSQDEFLTQDVLKELRWLVEFY 186

Myb-like DNA-binding domain; This family contains the DNA binding domains from Myb proteins, as well as the SANT domain family.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1927246371 107 RWSKQEKELFEQGLAQFGRRWTKIAKLVGSRSVLQVKSYARQYF 150
Cdd:pfam00249   3 PWTPEEDELLLEAVEKLGNRWKKIAKLLPGRTDNQCKNRWQNYL 46

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 1927246371 548 QAPFQVIVCAETLLIMDMHAHVSRGEVIGLLGGMFNEEEKVLKICAAEPCNSVSTGLQCEMDPLSQTQACDVLSSLGFSV 627
Cdd:cd08067     2 IQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLTGLDCEMDPVSETEIRESLESRGLSV 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1927246371 628 VGWYHSHPSFHPNPSVRDIATQDQFQSYFS---RGGAPFIGMIVSPYDPANRSPHSQTTCLLVKESQEP-SGPQKLPYRF 703
Cdd:cd08067    82 VGWYHSHPTFPPNPSLRDIDTQLDYQIMFKgsdSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENrPNEYGVPMLM 161

                         170       180
                  ....*....|....*....|....*
gi 1927246371 704 DFLSSQDIPDWEQTLRRAQWIIHKY 728
Cdd:cd08067   162 SYTVSQDEFLTQDVLKELRWLVEFY 186

Myb-like DNA-binding domain; This family contains the DNA binding domains from Myb proteins, as well as the SANT domain family.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1927246371 107 RWSKQEKELFEQGLAQFGRRWTKIAKLVGSRSVLQVKSYARQYF 150
Cdd:pfam00249   3 PWTPEEDELLLEAVEKLGNRWKKIAKLLPGRTDNQCKNRWQNYL 46

SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1927246371  107 RWSKQEKELFEQGLAQFG-RRWTKIAKLVGSRSVLQVKSYARQYFK 151
Cdd:smart00717   3 EWTEEEDELLIELVKKYGkNNWEKIAKELPGRTAEQCRERWRNLLK 48

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 1927246371  560 LLIMDMHAHVSRG---EVIGLLGGMFNEEekVLKICAAEPCNSVSTGLQCEMDPLSQTQACDVLSSL---GFSVVGWYHS 633
Cdd:smart00232   7 LVPLNILKHAIRDgpeEVCGVLLGKSNKD--RPEVKEVFAVPNEPQDDSVQEYDEDYSHLMDEELKKvnkDLEIVGWYHS 84

                           90       100
                   ....*....|....*....|..
gi 1927246371  634 HPSFHPNPSVRDIATQDQFQSY 655
Cdd:smart00232  85 HPDESPFPSEVDVATHESYQAP 106

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 1927246371 548 QAPFQVIVcaETLLIMDMHAHVSRG-----EVIGLLGGmFNEEEKVLKI--CAAEPCN----SVSTGLQCEMDPLSQTQA 616
Cdd:pfam01398   1 SSVRTVII--HPLVLLKILDHANRGgkigeEVMGVLLG-KLEGDGTIEItnSFALPQEetedDVNAVALDQEYMENMHEM 77

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1927246371 617 CDVLSSlGFSVVGWYHSHPSFhPNPSVRDIATQDQFQSY 655
Cdd:pfam01398  78 LKKVNR-KEEVVGWYHTHPGL-CWLSSVDVHTHALYQRM 114

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 1927246371 548 QAPFQVIVCAETLLIMDMHAHVSRGEVIGLLGGMFNEEEKVLKICAAEPCNSVSTGLQCEMDPLSQTQACDVLSSLGFSV 627
Cdd:cd08067     2 IQPFKVTVSSNALLLMDFHCHLTTSEVIGYLGGTWDPNTQNLTILQAFPCRSRLTGLDCEMDPVSETEIRESLESRGLSV 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1927246371 628 VGWYHSHPSFHPNPSVRDIATQDQFQSYFS---RGGAPFIGMIVSPYDPANRSPHSQTTCLLVKESQEP-SGPQKLPYRF 703
Cdd:cd08067    82 VGWYHSHPTFPPNPSLRDIDTQLDYQIMFKgsdSGYEPCVGLICSPYDRRNSTPESQITCFWVMPPPENrPNEYGVPMLM 161

                         170       180
                  ....*....|....*....|....*
gi 1927246371 704 DFLSSQDIPDWEQTLRRAQWIIHKY 728
Cdd:cd08067   162 SYTVSQDEFLTQDVLKELRWLVEFY 186

SWIRM domain; This SWIRM domain is a small alpha-helical domain of about 85 amino acid residues found in chromosomal proteins. It contains a helix-turn helix motif and binds to DNA.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1927246371 369 KQAIPEFFEGRpSKTPERYLKIRNYILDQWLKSKPKYLNKTSVRPGLknCGDVNCIGRIHTYLELIGAINF 439
Cdd:pfam04433  11 KRLLPEFFNGK-SKTPEVYLEIRNFILNLWRENPKEYLTKTDARRAL--KGDVNLISRIHEFLERWGLINF 78

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 1927246371 552 QVIVCAETLLIMDMHAhvSRG---EVIGLLGGMFNEEEKVLKICAAEPcnsVS-TGLQCEMDPLSQTQACD--VLSSLGF 625
Cdd:cd08069    11 KVYISSLALLKMLKHA--RAGgpiEVMGLMLGKVDDYTIIVVDVFALP---VEgTETRVNAQDEFQEYMVQyeMLKQTGR 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1927246371 626 --SVVGWYHSHPSFHPNPSVRDIATQDQFQsyfsRGGAPFIGMIVSP 670
Cdd:cd08069    86 peNVVGWYHSHPGYGCWLSGIDVNTQQLNQ----QLQDPFVAVVVDP 128

SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1927246371  107 RWSKQEKELFEQGLAQFG-RRWTKIAKLVGSRSVLQVKSYARQYFK 151
Cdd:smart00717   3 EWTEEEDELLIELVKKYGkNNWEKIAKELPGRTAEQCRERWRNLLK 48

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 1927246371  560 LLIMDMHAHVSRG---EVIGLLGGMFNEEekVLKICAAEPCNSVSTGLQCEMDPLSQTQACDVLSSL---GFSVVGWYHS 633
Cdd:smart00232   7 LVPLNILKHAIRDgpeEVCGVLLGKSNKD--RPEVKEVFAVPNEPQDDSVQEYDEDYSHLMDEELKKvnkDLEIVGWYHS 84

                           90       100
                   ....*....|....*....|..
gi 1927246371  634 HPSFHPNPSVRDIATQDQFQSY 655
Cdd:smart00232  85 HPDESPFPSEVDVATHESYQAP 106

RSC chromatin remodeling complex subunit RSC8 [Chromatin structure and dynamics / Transcription];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1927246371 369 KQAIPEFFEGR-PSKTPERYLKIRNYILDQWLKSKPKYLNKTSVRPGLknCGDVNCIGRIHTYLELIGAINF 439
Cdd:COG5259    71 KRSNPEFFNGRsPSKTPEVYKDYRNFMINSYRLNPNEYLTVTACRRNV--AGDVAAIVRVHRFLEKWGLINY 140

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 1927246371 566 HAHVSRG-EVIGLLGGMFNEEEKVLKICAAEPcnsVSTGLQcEMDPLSQTQACDVLSSLGFSVVGWYHSHPSFHPNPSVR 644
Cdd:cd07767     7 AAKSINGkEVIGLLYGSKTKKVLDVDEVIAVP---FDEGDK-DDNVWFLMYLDFKKLNAGLRIVGWYHTHPKPSCFLSPN 82

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1927246371 645 DIATQDQFQSYFsrGGAPFIGMIVSPYDPANR 676
Cdd:cd07767    83 DLATHELFQRYF--PEKVMIIVDVKPKDLGNS 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1927246371 565 MHAHVSRG---EVIGLLGGMFNEEEKVLKICAAEPCNSVStglqcEMDPLSQTQACDVLSSLGFSVVGWYHSHPSFHPNP 641
Cdd:pfam14464   8 IVAHARAAhplECCGILLGNELESQSVRVIPLVNPMRNRF-----EIDPGDSLRRVKAARERGLELVGIYHSHPGGPAYP 82

                  ....*.
gi 1927246371 642 SVRDIA 647
Cdd:pfam14464  83 SETDRR 88

BRISC complex subunit Abraxas 2 found in insects; BRISC complex subunit Abraxas 2 is also known as ABRO1, FAM175B or KIAA0157. The BRISC complex consists of BRCC36, MERIT40, BRE, and Abraxas 2, and serves cellular stress response and immune signaling functions; it specifically cleaves 'Lys-63'-linked polyubiquitin, leaving the last ubiquitin chain attached to its substrates; BRISC's catalytic subunit is the deubiquitinase (DUB) BRCC36. BRCC36 associates with pseudo-DUB protein Abraxas2, which lacks the essential Zn2+-coordinating residues required for DUB catalytic function. Higher-order association of BRCC36 and Abraxas2 into a dimer of heterodimers (superdimer) is required for BRCC36 DUB activity. In the BRISC complex, Abraxas 2 binds SHMT2a, a metabolic enzyme enabling cancer growth in hypoxic environments, which prevents the BRCC36 from binding and cleaving ubiquitin chains. BRCC36 in BRISC is activated by assembly due to interaction between Glu30 of BRCC36 and Asn164 in Abraxas 2 which structures the activation loop and positions the catalytic Glu33. The members in this subfamily include Camponotus floridanus KIAA0157 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1927246371 618 DVLSSLGFSVVGWYHSHPSFHPNPSVRDIATQDQFQSYFSrggapfigmivspydpANRSPHSQTTCLLVKESQEPSGPQ 697
Cdd:cd23525    82 DFLGDKSKQVVGWYKFRRNSSLKPTLRDKLLHKQLASYFS----------------KIHSKEFFVTCLLSSSVSENGSTH 145

                  ....*.
gi 1927246371 698 KLPYRF 703
Cdd:cd23525   146 KFRHVF 151