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 1237937652 254 LRHVVVPGRLCPQFLQLASANTARGVETCGILCGKLMRNEFTITHVLIPKQSAGSDYCNTENEEELFLIQDQQGLITLGW 333
Cdd:cd08066     1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1237937652 334 IHTHPTQTAFLSSVDLHTHCSYQMMLPESVAIVCSPKFQETGFFKLTD-HGLEEISSCRQKGFHPHSKDPPLF 405
Cdd:cd08066    81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTDpPGLDEILNCKKTGFHPHPKDPPLY 153

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 1237937652 254 LRHVVVPGRLCPQFLQLASANTARGVETCGILCGKLMRNEFTITHVLIPKQSAGSDYCNTENEEELFLIQDQQGLITLGW 333
Cdd:cd08066     1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1237937652 334 IHTHPTQTAFLSSVDLHTHCSYQMMLPESVAIVCSPKFQETGFFKLTD-HGLEEISSCRQKGFHPHSKDPPLF 405
Cdd:cd08066    81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTDpPGLDEILNCKKTGFHPHPKDPPLY 153

USP8 dimerization domain; This domain is predominantly found in the amino terminal region of Ubiquitin carboxyl-terminal hydrolase 8 (USP8). It forms a five helical bundle that dimerizes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1237937652  13 DRVRALSQLGSAVEVNEDIPPRRYFRSGVEIIRMASIYSEEGNIEHAFILYNKYITLFiEKLPKHRDYKSAVIPEKK-DT 91
Cdd:pfam08969  10 SSLEDLEKLTEKLEVDKNKSPKRYYRSALKLYKTAEEYRLEGDEENAYILYMKYFNLF-EKIRKHPDYKSVKATVRQmLG 88

                          90       100
                  ....*....|....*....|....*.
gi 1237937652  92 VKKLKEIaFPKAEELKAELLKRYTKE 117
Cdd:pfam08969  89 KTKINEV-LDELEKLKTSLLERYEEE 113

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 1237937652 280 ETCGILCGKlMRNEFTITHVLIPKQSAGSDYCNTE-NEEELFLIQ---DQQGLITLGWIHTHPTQTAFLSSVDLHthcsy 355
Cdd:COG1310    23 ECCGLLLGK-GGGDKRVTRVYPARNVAESPETRFEiDPEDLLAAEreaRERGLEIVGIYHSHPDGPAYPSETDRA----- 96

                          90       100       110
                  ....*....|....*....|....*....|
gi 1237937652 356 QMMLPESVAIVCSP--KFQETGFFKLTDHG 383
Cdd:COG1310    97 QAAWPGLPYLIVSLpdGGPELRAWRLRDGR 126

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 1237937652 254 LRHVVVPGRLCPQFLQLASANTARGVETCGILCGKLMRNEFTITHVLIPKQSAGSDYCNTENEEELFLIQDQQGLITLGW 333
Cdd:cd08066     1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1237937652 334 IHTHPTQTAFLSSVDLHTHCSYQMMLPESVAIVCSPKFQETGFFKLTD-HGLEEISSCRQKGFHPHSKDPPLF 405
Cdd:cd08066    81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTDpPGLDEILNCKKTGFHPHPKDPPLY 153

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 1237937652 264 CPQFLQLAsaNTARGVETCGILCGKLMRNEFTITHVLIPKQSAGSDYCNTENEEELFLIQDQQGLITLGWIHTHPTQTAF 343
Cdd:cd07767     1 LKMFLDAA--KSINGKEVIGLLYGSKTKKVLDVDEVIAVPFDEGDKDDNVWFLMYLDFKKLNAGLRIVGWYHTHPKPSCF 78

                          90       100
                  ....*....|....*....|....*..
gi 1237937652 344 LSSVDLHTHCSYQMMLPESVAIVCSPK 370
Cdd:cd07767    79 LSPNDLATHELFQRYFPEKVMIIVDVK 105

USP8 dimerization domain; This domain is predominantly found in the amino terminal region of Ubiquitin carboxyl-terminal hydrolase 8 (USP8). It forms a five helical bundle that dimerizes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1237937652  13 DRVRALSQLGSAVEVNEDIPPRRYFRSGVEIIRMASIYSEEGNIEHAFILYNKYITLFiEKLPKHRDYKSAVIPEKK-DT 91
Cdd:pfam08969  10 SSLEDLEKLTEKLEVDKNKSPKRYYRSALKLYKTAEEYRLEGDEENAYILYMKYFNLF-EKIRKHPDYKSVKATVRQmLG 88

                          90       100
                  ....*....|....*....|....*.
gi 1237937652  92 VKKLKEIaFPKAEELKAELLKRYTKE 117
Cdd:pfam08969  89 KTKINEV-LDELEKLKTSLLERYEEE 113

Mov34/MPN/PAD-1 family: BRCC36, a subunit of BRCA1-A complex; BRCC36 (BRCA1-A complex subunit BRCC36; BRCA1/BRCA2-containing complex subunit 36; BRCA1/BRCA2-containing complex subunit 3; BRCC3; BRISC complex subunit BRCC36; BRCC36 isopeptidase complex; Lys-63-specific deubiquitinase BRCC36) and BRCC36-like domains are members of JAMM/MPN+ deubiquitinases (DUBs), possibly with Zn2+-dependent ubiquitin isopeptidase activity. 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; RAP80 recruits the Abraxas-BRCC36-BRCA1-BARD1 complex to DNA double strand breaks (DSBs) for DNA repair through specific recognition of Lys 63-linked polyubiquitinated proteins by its tandem ubiquitin-interacting motifs. A new protein, MERIT40 (mediator of RAP80 interactions and targeting 40 kDa), also named NBA1 (new component of the BRCA1 A complex), exists in the same BRCA1-containing complex and is essential for the integrity of the complex. There are studies suggesting that MERIT40/NBA1 ties BRCA1 complex integrity, DSB recognition, and ubiquitin chain activities to the DNA damage response. It has also been shown that BRCA1-containing complex resembles the lid complex of the 26S proteasome.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1237937652 331 LGWIHTHPTQTAFLSSVDLHTHCSYQMMLPESVAIVCS 368
Cdd:cd08068    92 VGWYHSHPHITVWPSHVDVRTQAMYQMMDSGFVGLIFS 129

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1237937652 316 EEELFLIQDQQGLITLGWIHTHPTQTAFLSSVDLHTHCSYQMMLPES-------VAIVCSP 369
Cdd:cd08067    67 ETEIRESLESRGLSVVGWYHSHPTFPPNPSLRDIDTQLDYQIMFKGSdsgyepcVGLICSP 127

Mpr1p, Pad1p N-terminal (MPN) domains without isopeptidase activity found in splicing factor Prp8; Members of this family are found in pre-mRNA-processing factor 8 (Prp8) which is a critical splicing factor, interacting with several other spliceosomal proteins, snRNAs, and the pre-mRNA, thus organizing and stabilizing the spliceosome catalytic core. Prp8 is one of the largest and most highly conserved of nuclear proteins, occupying a central position in the catalytic core of the spliceosome. Its C-terminal domain exhibits a JAB1/MPN-like core similar to deubiquitinating enzymes, but does not show catalytic isopeptidase activity, possibly because the putative isopeptidase center is covered by insertions and terminal appendices that are grafted onto this core, thus impairing the metal binding site. It is proposed that this domain is a protein interaction domain instead of a Zn(2+)-dependent metalloenzyme as proposed for some MPN proteins. The DEAD-box protein Brr2 and the GTPase Snu114 bind to the Prp8 C-terminus, a region where mutations in human Prp8 (hPrp8) cause a severe form of the genetic disorder retinitis pigmentosa, RP13, which leads to progressive photoreceptor degeneration in the retina and eventual blindness. At the N-terminus of Prp8, there are several domains, including a highly variable nuclear localization signal (NLS) motif rich in prolines, a conserved RNA recognition motif (RRM), and U5 and U6 snRNA binding sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1237937652 326 QGLITLGWIHTHPTQTAFLSSVDLHTH-------------------CSYQmmlPESVAIVCspkfqetgfFKLTDHGLE- 385
Cdd:cd08056   104 EDLEPLGWIHTQPNELPQLSPQDVTTHakiladnpswdgektviltCSFT---PGSCSLTA---------YKLTPEGYEw 171

                          90
                  ....*....|....*..
gi 1237937652 386 -----EISSCRQKGFHP 397
Cdd:cd08056   172 gkqnkDLGNNTPKGYSP 188