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 169234828 266 LRCVVLSRDLCHKFLLLADSNTVRGIETCGILCGKLTHNEFTITHVVVPKQSAGPDYCDVENVEELFSVQDQHGLLTLGW 345
Cdd:cd08066    1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 169234828 346 IHTHPTQTAFLSSVDLHTHCSYQLMLPEAIAIVCSPKHKDTGIFRLT-NAGMLEVSTCKKKGFHPHTKDPKLFSICSHVL 424
Cdd:cd08066   81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTdPPGLDEILNCKKTGFHPHPKDPPLYEDCGHVI 160

                        170
                 ....*....|...
gi 169234828 425 VKD-IKTTVLDLR 436
Cdd:cd08066  161 WKDqLKVTVVDLR 173

Periplasmic chaperone for outer membrane proteins, Skp family [Cell wall/membrane/envelope biogenesis, Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 169234828 101 PEKQDIMKKLKEIAFPRTDELKTdLLRKYNIEYQEYLQSKNKYKAEILKKLEhQRLIEAER--QRIAQMRQQQLESEQ 176
Cdd:COG2825   39 PEGKAAQKKLEKEFKKRQAELQK-LEKELQALQEKLQKEAATLSEEERQKKE-RELQKKQQelQRKQQEAQQDLQKRQ 114

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 169234828 266 LRCVVLSRDLCHKFLLLADSNTVRGIETCGILCGKLTHNEFTITHVVVPKQSAGPDYCDVENVEELFSVQDQHGLLTLGW 345
Cdd:cd08066    1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 169234828 346 IHTHPTQTAFLSSVDLHTHCSYQLMLPEAIAIVCSPKHKDTGIFRLT-NAGMLEVSTCKKKGFHPHTKDPKLFSICSHVL 424
Cdd:cd08066   81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTdPPGLDEILNCKKTGFHPHPKDPPLYEDCGHVI 160

                        170
                 ....*....|...
gi 169234828 425 VKD-IKTTVLDLR 436
Cdd:cd08066  161 WKDqLKVTVVDLR 173

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 169234828   28 ERVRALSKLGCNISINEDITPRRYFRSGVEMERMASVYLEEGNLENAFVLYNKFITLFvEKLPSHRDYQQCAVPEKQDIM 107
Cdd:pfam08969  10 SSLEDLEKLTEKLEVDKNKSPKRYYRSALKLYKTAEEYRLEGDEENAYILYMKYFNLF-EKIRKHPDYKSVKATVRQMLG 88

                          90       100
                  ....*....|....*....|....*
gi 169234828  108 KKLKEIAFPRTDELKTDLLRKYNIE 132
Cdd:pfam08969  89 KTKINEVLDELEKLKTSLLERYEEE 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 169234828 269 VVLSRDLCHKFLLLADSNTVRgiETCGILCGKLThNEFTITHVVVpkqsagpdycdVENV------------EELFSVQ- 335
Cdd:COG1310    2 LVLPRELLDAILAHAEAAYPE--ECCGLLLGKGG-GDKRVTRVYP-----------ARNVaespetrfeidpEDLLAAEr 67

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 169234828 336 --DQHGLLTLGWIHTHPTQTAFLSSVDLhTHCSYqlmlPEAIAIVCSPKHK--DTGIFRLTN 393
Cdd:COG1310   68 eaRERGLEIVGIYHSHPDGPAYPSETDR-AQAAW----PGLPYLIVSLPDGgpELRAWRLRD 124

Outer membrane protein (OmpH-like); This family includes outer membrane proteins such as OmpH among others. Skp (OmpH) has been characterized as a molecular chaperone that interacts with unfolded proteins as they emerge in the periplasm from the Sec translocation machinery.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 169234828  101 PEKQDIMKKLKEIAFPRTDELKTdLLRKYNIEYQEYLQSKNKYKAEILKKL-EHQRLiEAERQRIAQMRQQQLESEQFLF 179
Cdd:pfam03938  15 PEGKAAQAQLEKKFKKRQAELEA-KQKELQKLYEELQKDGALLEEEREEKEqELQKK-EQELQQLQQKAQQELQKKQQEL 92

                  ....*..
gi 169234828  180 FEDQLKK 186
Cdd:pfam03938  93 LQPIQDK 99

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 169234828 266 LRCVVLSRDLCHKFLLLADSNTVRGIETCGILCGKLTHNEFTITHVVVPKQSAGPDYCDVENVEELFSVQDQHGLLTLGW 345
Cdd:cd08066    1 LRQVVVPADLMDKFLQLAEPNTSRNLETCGILCGKLSNNAFFITHLIIPKQSGTSDSCQTTNEEELFDFQDQHDLITLGW 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 169234828 346 IHTHPTQTAFLSSVDLHTHCSYQLMLPEAIAIVCSPKHKDTGIFRLT-NAGMLEVSTCKKKGFHPHTKDPKLFSICSHVL 424
Cdd:cd08066   81 IHTHPTQTCFLSSVDLHTHCSYQLMLPEAIAIVCAPKYNEFGIFRLTdPPGLDEILNCKKTGFHPHPKDPPLYEDCGHVI 160

                        170
                 ....*....|...
gi 169234828 425 VKD-IKTTVLDLR 436
Cdd:cd08066  161 WKDqLKVTVVDLR 173

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 169234828 276 CHKFLLLADSNtvRGIETCGILCGKLTHNEFTITHVVVPKQSAGPDYCDVENVEELFSVQDQHGLLTLGWIHTHPTQTAF 355
Cdd:cd07767    1 LKMFLDAAKSI--NGKEVIGLLYGSKTKKVLDVDEVIAVPFDEGDKDDNVWFLMYLDFKKLNAGLRIVGWYHTHPKPSCF 78

                         90       100       110
                 ....*....|....*....|....*....|..
gi 169234828 356 LSSVDLHTHCSYQLMLPEAIAIVCSPKHKDTG 387
Cdd:cd07767   79 LSPNDLATHELFQRYFPEKVMIIVDVKPKDLG 110

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 169234828   28 ERVRALSKLGCNISINEDITPRRYFRSGVEMERMASVYLEEGNLENAFVLYNKFITLFvEKLPSHRDYQQCAVPEKQDIM 107
Cdd:pfam08969  10 SSLEDLEKLTEKLEVDKNKSPKRYYRSALKLYKTAEEYRLEGDEENAYILYMKYFNLF-EKIRKHPDYKSVKATVRQMLG 88

                          90       100
                  ....*....|....*....|....*
gi 169234828  108 KKLKEIAFPRTDELKTDLLRKYNIE 132
Cdd:pfam08969  89 KTKINEVLDELEKLKTSLLERYEEE 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 169234828 269 VVLSRDLCHKFLLLADSNTVRgiETCGILCGKLThNEFTITHVVVpkqsagpdycdVENV------------EELFSVQ- 335
Cdd:COG1310    2 LVLPRELLDAILAHAEAAYPE--ECCGLLLGKGG-GDKRVTRVYP-----------ARNVaespetrfeidpEDLLAAEr 67

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 169234828 336 --DQHGLLTLGWIHTHPTQTAFLSSVDLhTHCSYqlmlPEAIAIVCSPKHK--DTGIFRLTN 393
Cdd:COG1310   68 eaRERGLEIVGIYHSHPDGPAYPSETDR-AQAAW----PGLPYLIVSLPDGgpELRAWRLRD 124

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 169234828 343 LGWIHTHPTQTAFLSSVDLHTHCSYQLMLPEAIAIVCS 380
Cdd:cd08068   92 VGWYHSHPHITVWPSHVDVRTQAMYQMMDSGFVGLIFS 129

Periplasmic chaperone for outer membrane proteins, Skp family [Cell wall/membrane/envelope biogenesis, Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 169234828 101 PEKQDIMKKLKEIAFPRTDELKTdLLRKYNIEYQEYLQSKNKYKAEILKKLEhQRLIEAER--QRIAQMRQQQLESEQ 176
Cdd:COG2825   39 PEGKAAQKKLEKEFKKRQAELQK-LEKELQALQEKLQKEAATLSEEERQKKE-RELQKKQQelQRKQQEAQQDLQKRQ 114

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 169234828 270 VLSRDLCHKFLLLADsntVRgIETCGILCGK-LTHNEFT--ITHVVVPkqsagPDYCDVENVEelFSVQ-DQHGLLT--- 342
Cdd:cd08056   39 ILPKNLLKKFISISD---LR-TQIAGYLYGKsPPDNPQVkeIRCIVLV-----PQLGTHQTVT--LPQQlPQHEYLEdle 107

                         90       100
                 ....*....|....*....|...
gi 169234828 343 -LGWIHTHPTQTAFLSSVDLHTH 364
Cdd:cd08056  108 pLGWIHTQPNELPQLSPQDVTTH 130