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 336285487  204 CLESAVELPKILCQEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLEQNQQHLQELQQEKEE 283
Cdd:pfam18110   1 CLESLTELPEILFQEEKEAYEKAKKSGSLDLLTKIHNGSVFTKSLCHITEAISGPLLQALEARLKLNKNRLAALKQEKEE 80

                  .
gi 336285487  284 L 284
Cdd:pfam18110  81 L 81

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 336285487  23 LNHALSTEKEEVMGLCIGELNDDtsrsdskfaytgtemRTVaekVDAVRIVHIHsviilrrsDKRKDRVEISPEQLSAAS 102
Cdd:COG1310   13 LAHAEAAYPEECCGLLLGKGGGD---------------KRV---TRVYPARNVA--------ESPETRFEIDPEDLLAAE 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 336285487 103 TEAERlaeltgRPMRVVGWYHSHPHITVWPSHVDVRtqamyQMMDQGFVGLIFS 156
Cdd:COG1310   67 REARE------RGLEIVGIYHSHPDGPAYPSETDRA-----QAAWPGLPYLIVS 109

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 336285487  17 DAFLVCLNHALSTEKEEVMGLCIGELNDDtsrsdskfaytgtemrtvaekvdavrivhihsviilRRSDKRKDRVEISPE 96
Cdd:cd08058    1 DALLKMLQHAESNTGIEVMGLLCGELTHN------------------------------------EFTDKHVIVPKQSAG 44

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 336285487  97 QLSAASTE-AERLAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDQGFVGLIFSCFIEdkNTKTGRVLYT 172
Cdd:cd08058   45 PDSCTGENvEELFNVQTGRPLLVVGWYHSHPTFTAWLSSVDIHTQASYQLMLPEAIAIVVSPKHR--NKDTGIFRLT 119

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 336285487    13 HLESDAFLVCLNHALSTEKEEVMGLCIGELNDDTsrsdskfaytgtemrtvaekvdavriVHIHSVIILRRsDKRKDRVE 92
Cdd:smart00232   3 KVHPLVPLNILKHAIRDGPEEVCGVLLGKSNKDR--------------------------PEVKEVFAVPN-EPQDDSVQ 55

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 336285487    93 ISPEQLSAASTEAERLaelTGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDQGFVGLIfscfIEDKNTKTGRVLYT 172
Cdd:smart00232  56 EYDEDYSHLMDEELKK---VNKDLEIVGWYHSHPDESPFPSEVDVATHESYQAPWPISVVLI----VDPIKSFQGRLSLR 128

                   ....*..
gi 336285487   173 CFQSIQA 179
Cdd:smart00232 129 AFRLTPE 135

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 336285487  23 LNHALSTEKEEVMGLCIGELNDDTSR-SDSkFAY--TGTEMRtvaekVDAVRIVHIHSViilrrsdkrkdrveispeqls 99
Cdd:cd08069   23 LKHARAGGPIEVMGLMLGKVDDYTIIvVDV-FALpvEGTETR-----VNAQDEFQEYMV--------------------- 75

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 336285487 100 aasteAERLAELTGRPMRVVGWYHSHPHITVWPSHVDVRTQAMYQMMDQGFVGL 153
Cdd:cd08069   76 -----QYEMLKQTGRPENVVGWYHSHPGYGCWLSGIDVNTQQLNQQLQDPFVAV 124

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 336285487  23 LNHALSTEKEEVMGLCIGELNDDtsrsdskfaytgtemRTVaekVDAVRIVHIHsviilrrsDKRKDRVEISPEQLSAAS 102
Cdd:COG1310   13 LAHAEAAYPEECCGLLLGKGGGD---------------KRV---TRVYPARNVA--------ESPETRFEIDPEDLLAAE 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 336285487 103 TEAERlaeltgRPMRVVGWYHSHPHITVWPSHVDVRtqamyQMMDQGFVGLIFS 156
Cdd:COG1310   67 REARE------RGLEIVGIYHSHPDGPAYPSETDRA-----QAAWPGLPYLIVS 109

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
                 ....*....|....*....|....*....|.
gi 336285487 116 MRVVGWYHSHPHITVWPSHVDVRTQAMYQMM 146
Cdd:cd07767   63 LRIVGWYHTHPKPSCFLSPNDLATHELFQRY 93

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
                 ....*....|....*....|....*...
gi 336285487 119 VGWYHSHPHITVWPSHVDVRTQAMYQMM 146
Cdd:cd08066   78 LGWIHTHPTQTCFLSSVDLHTHCSYQLM 105