Rcat domain found in the RNF144 protein subfamily; The RNF144 subfamily includes RNF144A and RNF144B, which are transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligases. RNF144A, also called UbcM4-interacting protein 4 (UIP4), or ubiquitin-conjugating enzyme 7-interacting protein 4, targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144B, also called PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), induces p53-dependent but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Both RNF144A and RNF144B contain an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of the RNF144 protein subfamily that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 184 DDAPIKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLESLDDDFLLIHYDKGPCRNKLGHSRASVIWHR 253
Cdd:cd20352     1 EDAPIKRCPMCHVPIERDEGCAQMMCKNCKHVFCWYCLASLDDDFLLRHYDKGPCKNKLGHSRASVIWHR 70

Modified RING finger, HC subclass (C4C4-type), found in RING finger protein 144A (RNF144A); RNF144A, also known as UbcM4-interacting protein 4 (UIP4) or ubiquitin-conjugating enzyme 7-interacting protein 4, is a transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligase that targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144A contains an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C4C4-type RING finger whose overall folding is similar to that of the C3HC4-type RING-HC finger. It is responsible for the interaction of E2-conjugating enzymes UbcH7 and UbcH8.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554  23 VSCKLCLGEFPLEQMTTITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSACPK 77
Cdd:cd16777     1 VSCKLCLGEYPVEQMTTIAQCQCIFCTLCLKQYVELLIKEGLETAISCPDAACPK 55

Disintegrin;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554 672 EEGEQCDPGLL-HLNDDPCCTP-TCKLKKGMHCSdrNSPCCSNCRFQEANKICQESINaTCKASSSCTGNSSECP 744
Cdd:pfam00200   1 EEGEECDCGSLeECTNDPCCDAkTCKLKPGAQCS--SGPCCTNCQFKPAGTVCRPSKD-ECDLPEYCNGTSAECP 72

Rcat domain found in the RNF144 protein subfamily; The RNF144 subfamily includes RNF144A and RNF144B, which are transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligases. RNF144A, also called UbcM4-interacting protein 4 (UIP4), or ubiquitin-conjugating enzyme 7-interacting protein 4, targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144B, also called PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), induces p53-dependent but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Both RNF144A and RNF144B contain an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of the RNF144 protein subfamily that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 184 DDAPIKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLESLDDDFLLIHYDKGPCRNKLGHSRASVIWHR 253
Cdd:cd20352     1 EDAPIKRCPMCHVPIERDEGCAQMMCKNCKHVFCWYCLASLDDDFLLRHYDKGPCKNKLGHSRASVIWHR 70

Metallo-peptidase family M12B Reprolysin-like; This zinc-binding metallo-peptidase has the characteriztic binding motif HExxGHxxGxxH of Reprolysin-like peptidases of family M12B.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 434 TTLNYLIELIDRVDDIYRntswDDEFKGYGVQIHQIIINKFPTQVDPgqlHYNMEGSPrpkdnqVWDVKKL--LEQFSSd 511
Cdd:pfam13574   2 NVTENLVNVVNRVNQIYE----PDDININGGLVNPGEIPATTSASDS---GNNYCNSP------TTIVRRLnfLSQWRG- 67

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 512 iadnASSVCLAHLFTYQDFDEGTLGLAYVassrdqalGGLCSKPYypvpsvkKASYLNTGLTSTKNYGKTILTKEADLVT 591
Cdd:pfam13574  68 ----EQDYCLAHLVTMGTFSGGELGLAYV--------GQICQKGA-------SSPKTNTGLSTTTNYGSFNYPTQEWDVV 128

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554 592 THELGHNFGAEHDPDNIAYCAP---------SDEQGGKFVMYPIAVSgdhpNNKRFSNCSKASVS 647
Cdd:pfam13574 129 AHEVGHNFGATHDCDGSQYASSgcernaatsVCSANGSFIMNPASKS----NNDLFSPCSISLIC 189

Membrane-proximal domain, switch, for ADAM17; ADAM17_MPD is the membrane-proximal domain of a family of disintegrin and metalloproteinase domain-containing protein 17 found in metazoan species. ADAM17 is a major sheddase that is responsible for the regulation of a wide range of biological processes, such as cellular differentiation, regeneration, and cancer progression. This MPD region acts as the sheddase switch. PDI or protein-disulfide isomerase interacts with ADAM17 and to down-regulate its enzymatic activity. The interaction is directly with the MPD, the region of dimerization and substrate recognition, where it catalyzes an isomerization of disulfide bridges within the thioredoxin motif CXXC. this isomerization results in a major structural change between an active, open state and an inactive, closed state of the MPD. This change is thought to act as a molecular switch, allowing a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878416554 769 FCEATPKLRSCACNDTDSSCKVCCK-KNGVCTPFKFDNGEYLYLRKGKPCTVGFCDGHGKCM 829
Cdd:pfam16698   1 FCETKSGLQSCACNETDDSCKVCCRdLNGTCSPYLDANGSFLYLRDGKPCTVGFCDGKGKCE 62

Disintegrin;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554 672 EEGEQCDPGLL-HLNDDPCCTP-TCKLKKGMHCSdrNSPCCSNCRFQEANKICQESINaTCKASSSCTGNSSECP 744
Cdd:pfam00200   1 EEGEECDCGSLeECTNDPCCDAkTCKLKPGAQCS--SGPCCTNCQFKPAGTVCRPSKD-ECDLPEYCNGTSAECP 72

In Between Ring fingers; the domains occurs between pairs og RING fingers

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1878416554   96 QRYRKLQFEKEVLLDPCRTWCPSSSCQAVCQLKEadSARPQLVRCGNCTLEFCSACKASWHPGQEC 161
Cdd:smart00647   1 EKYERLLLESYVESNPDLKWCPAPDCSAAIIVTE--EEGCNRVTCPKCGFSFCFRCKVPWHSPVSC 64

Myxococcus cysteine-rich repeat; This model represents a sequence region shared between several proteins of Myxococcus xanthus DK 1622 and some eukaryotic proteins that include human pappalysin-1 (SP|Q13219). The region of about 40 amino acids contains several conserved Cys residues presumed to form disulfide bonds. The region appears in up to 13 repeats in Myxococcus.

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 1878416554 666 CGNSRVEEGEQCDPGLLHLNDDpcCTPTCKLKKGMHC 702
Cdd:TIGR02232   4 CGDGIIEPGEECDDGNTTSGDG--CSATCRLEEGFAC 38

Rcat domain found in the RNF144 protein subfamily; The RNF144 subfamily includes RNF144A and RNF144B, which are transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligases. RNF144A, also called UbcM4-interacting protein 4 (UIP4), or ubiquitin-conjugating enzyme 7-interacting protein 4, targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144B, also called PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), induces p53-dependent but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Both RNF144A and RNF144B contain an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of the RNF144 protein subfamily that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 184 DDAPIKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLESLDDDFLLIHYDKGPCRNKLGHSRASVIWHR 253
Cdd:cd20352     1 EDAPIKRCPMCHVPIERDEGCAQMMCKNCKHVFCWYCLASLDDDFLLRHYDKGPCKNKLGHSRASVIWHR 70

Zinc-dependent metalloprotease, ADAM_like or reprolysin_like subgroup. The adamalysin_like or ADAM family of metalloproteases contains proteolytic domains from snake venoms, proteases from the mammalian reproductive tract, and the tumor necrosis factor alpha convertase, TACE. ADAMs (A Disintegrin And Metalloprotease) are glycoproteins, which play roles in cell signaling, cell fusion, and cell-cell interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 411 NTCTLLLVADYRFYKHMGREEESTTlNYLIELIDRVDDIYRNTswdDEFKGYGVQIHQIIINKFPTQVDPGQlhynmegs 490
Cdd:cd04267     1 REIELVVVADHRMVSYFNSDENILQ-AYITELINIANSIYRST---NLRLGIRISLEGLQILKGEQFAPPID-------- 68

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 491 prpkdnqvWDVKKLLEQFSSDIADNASSVCLAHLFTYQDFDEG-TLGLAYVassrdqalGGLCSkpyypvpsvkkaSYLN 569
Cdd:cd04267    69 --------SDASNTLNSFSFWRAEGPIRHDNAVLLTAQDFIEGdILGLAYV--------GSMCN------------PYSS 120

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 570 TGLTSTKNYgktilTKEADLVTTHELGHNFGAEHDPDNIayCAPSDEQGGKFVMYPIAVSGdhpNNKRFSNCSKASVSRT 649
Cdd:cd04267   121 VGVVEDTGF-----TLLTALTMAHELGHNLGAEHDGGDE--LAFECDGGGNYIMAPVDSGL---NSYRFSQCSIGSIREF 190

                  ..
gi 1878416554 650 LK 651
Cdd:cd04267   191 LD 192

BRcat domain found in RING finger protein 144A (RNF144A); RNF144A, also called UbcM4-interacting protein 4 (UIP4) or ubiquitin-conjugating enzyme 7-interacting protein 4, is a transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligase that targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144A contains an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the BRcat domain of RNF144A that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554 104 EKEVLLDPCRTWCPSSSCQAVCQLKEADSARPQLVRCGNCTLEFCSACKASWHPGQECQENPPIT 168
Cdd:cd20366     1 EREVLLDPCRTWCPSSTCQAVCQLQEVGLQNPQLVQCKACDLEFCSACKANWHPGQGCQENMPIT 65

Modified RING finger, HC subclass (C4C4-type), found in RING finger protein 144A (RNF144A); RNF144A, also known as UbcM4-interacting protein 4 (UIP4) or ubiquitin-conjugating enzyme 7-interacting protein 4, is a transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligase that targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and thus promotes DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144A contains an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C4C4-type RING finger whose overall folding is similar to that of the C3HC4-type RING-HC finger. It is responsible for the interaction of E2-conjugating enzymes UbcH7 and UbcH8.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554  23 VSCKLCLGEFPLEQMTTITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSACPK 77
Cdd:cd16777     1 VSCKLCLGEYPVEQMTTIAQCQCIFCTLCLKQYVELLIKEGLETAISCPDAACPK 55

BRcat domain found in RING finger protein 144B (RNF144B); RNF144B, also called PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), is a transmembrane (TM) domain-containing RBR E3 ubiquitin-protein ligase that induces p53-dependent but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. RNF144B contains an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the BRcat domain of RNF144B that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1878416554 106 EVLLDPCRTWCPSSSCQAVCQLKEADSARPQLVRCGNCTLEFCSACKASWHPGQECQENPPITA 169
Cdd:cd20367     1 EVHLDPCRTWCPVADCQTVCHVEASDSGQPVLVECPSCHLKFCSVCKDAWHPEHSCQESQPIVL 64

Zinc-dependent metalloprotease; adamalysin_II_like subfamily. Adamalysin II is a snake venom zinc endopeptidase. This subfamily contains other snake venom metalloproteinases, as well as membrane-anchored metalloproteases belonging to the ADAM family. ADAMs (A Disintegrin And Metalloprotease) are glycoproteins, which play roles in cell signaling, cell fusion, and cell-cell interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 415 LLLVADYRFYKHMGREEeSTTLNYLIELIDRVDDIYRNtswddefkgygVQIHQIII--------NKFPTQVDPGQ-LHY 485
Cdd:cd04269     5 LVVVVDNSLYKKYGSNL-SKVRQRVIEIVNIVDSIYRP-----------LNIRVVLVgleiwtdkDKISVSGDAGEtLNR 72

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 486 NMEgsprpkdnqvWDVKKLLEQFSSDIAdnassvclaHLFTYQDFDEGTLGLAYVassrdqalGGLCSKPYypvpSVKKA 565
Cdd:cd04269    73 FLD----------WKRSNLLPRKPHDNA---------QLLTGRDFDGNTVGLAYV--------GGMCSPKY----SGGVV 121

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 566 SYLNTGLTStknygktiltkeADLVTTHELGHNFGAEHDpDNIAYCapsdeQGGKFVMYPIAVSGdhpnNKRFSNCSKAS 645
Cdd:cd04269   122 QDHSRNLLL------------FAVTMAHELGHNLGMEHD-DGGCTC-----GRSTCIMAPSPSSL----TDAFSNCSYED 179

                         250
                  ....*....|..
gi 1878416554 646 VSRTLKVKAPQC 657
Cdd:cd04269   180 YQKFLSRGGGQC 191

Modified RING finger, HC subclass (C4C4-type), found in RNF144 proteins; This group includes RNF144A and RNF144B, both of which are transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligases. RNF144A, also known as UbcM4-interacting protein 4 (UIP4) or ubiquitin-conjugating enzyme 7-interacting protein 4, targets DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and thus promote DNA damage-induced cell apoptosis. It is transcriptionally repressed by metastasis-associated protein 1 (MTA1) and inhibits MTA1-driven cancer cell migration and invasion. RNF144B, also known as PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), induces p53-dependent but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Both RNF144A and RNF144B contain an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C4C4-type RING finger whose overall folding is similar to that of the C3HC4-type RING-HC finger. It is required for RBR-mediated ubiquitination.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1878416554  23 VSCKLCLGEFPLEQMTTITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSAC 75
Cdd:cd16632     1 ITCKLCLEEVPLREMYTLQSCGCIFCLQCLKQYVEVLIREGNVSSITCPDAAC 53

Disintegrin;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554 672 EEGEQCDPGLL-HLNDDPCCTP-TCKLKKGMHCSdrNSPCCSNCRFQEANKICQESINaTCKASSSCTGNSSECP 744
Cdd:pfam00200   1 EEGEECDCGSLeECTNDPCCDAkTCKLKPGAQCS--SGPCCTNCQFKPAGTVCRPSKD-ECDLPEYCNGTSAECP 72

Modified RING finger, HC subclass (C4C4-type), found in RING finger protein 144B (RNF144B); RNF144B, also known as PIR2, IBR domain-containing protein 2 (IBRDC2), or p53-inducible RING finger protein (p53RFP), is a transmembrane (TM) domain-containing RBR (RING1-IBR-RING2) E3 ubiquitin-protein ligase that induces p53-dependent, but caspase-independent apoptosis. It interacts with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8, but not with UbcH5. It is involved in ubiquitination and degradation of p21, a p53 downstream protein promoting growth arrest and antagonizing apoptosis, suggesting a role in switching a cell from p53-mediated growth arrest to apoptosis. Moreover, RNF144B regulates the levels of Bax, a pro-apoptotic protein from the Bcl-2 family, and protects cells from unprompted Bax activation and cell death. It also regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. RNF144B contains an RBR domain followed by a potential single-TM domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C4C4-type RING finger whose overall folding is similar to that of the C3HC4-type RING-HC finger. It is required for RBR-mediated ubiquitination.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1878416554  23 VSCKLCLGEFPLEQMTTITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSACPKRG 79
Cdd:cd16778     1 VTCKLCLCEHPFDAMTTLQECDCVFCTPCLKQYVQLAIREGCGSPITCPDMACTKTG 57

Reprolysin (M12B) family zinc metalloprotease; The members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis. Members of this family are also known as adamalysins. Most members of this family are snake venom endopeptidases, but there are also some mammalian proteins such as Swiss:P78325, and fertilin. Fertilin and closely related proteins appear to not have some active site residues and may not be active enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 415 LLLVADYRFYKHMGREEESTTlNYLIELIDRVDDIYR--NTS--------WDDEfkgygvqihqiiiNKFPTQVDPGQLH 484
Cdd:pfam01421   5 LFIVVDKQLFQKMGSDTTVVR-QRVFQVVNLVNSIYKelNIRvvlvgleiWTDE-------------DKIDVSGDANDTL 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 485 YNMegsprpkdnQVWDVKKLLEQFSSDIAdnassvclaHLFTYQDFDEGTLGLAYVassrdqalGGLCSkPYYPVpSVKK 564
Cdd:pfam01421  71 RNF---------LKWRQEYLKKRKPHDVA---------QLLSGVEFGGTTVGAAYV--------GGMCS-LEYSG-GVNE 122

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 565 ASYLNTGLTSTknygktiltkeadlVTTHELGHNFGAEHDPDNIA-YCAPsdeqGGKFVMYPIAVsgdHPNNKRFSNCSK 643
Cdd:pfam01421 123 DHSKNLESFAV--------------TMAHELGHNLGMQHDDFNGGcKCPP----GGGCIMNPSAG---SSFPRKFSNCSQ 181

                         250
                  ....*....|....
gi 1878416554 644 ASVSRTLKVKAPQC 657
Cdd:pfam01421 182 EDFEQFLTKQKGAC 195

Rcat domain found in RING finger protein 14 (RNF14); RNF14, also called androgen receptor (AR)-associated protein 54 (ARA54), HFB30, or Triad2 protein, is an RBR-type E3 ubiquitin-protein ligase that is highly expressed in the testis and interacts with class III E2s (UBE2E2, UbcH6, and UBE2E3). Its differential localization may play an important role in testicular development and spermatogenesis in humans. RNF14 functions as a transcriptional regulator of mitochondrial and immune function in muscles. It is a ligand-dependent AR co-activator that enhances AR-dependent transcriptional activation. It also may participate in enhancing cell cycle progression and cell proliferation via induction of cyclin D1. Moreover, RNF14 is crucial for colon cancer cell survival. It acts as a new enhancer of the Wnt-dependent transcriptional outputs that acts at the level of the T-cell factor/lymphoid enhancer factor (TCF/LEF)-beta-catenin complex. RNF14 contains an N-terminal RWD domain, and a C-terminal RBR domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of RNF14 that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1878416554 188 IKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLESLDDDFLLIHY--DKGPCRNK 241
Cdd:cd20354    13 SKPCPGCGTLIEKIDGCNKMTCTKCRTYFCWLCLKVLSRTNPYSHFsdPNSPCFNR 68

IBR domain, a half RING-finger domain; The IBR (In Between Ring fingers) domain is often found to occur between pairs of ring fingers (pfam00097). This domain has also been called the C6HC domain and DRIL (for double RING finger linked) domain. Proteins that contain two Ring fingers and an IBR domain (these proteins are also termed RBR family proteins) are thought to exist in all eukaryotic organizms. RBR family members play roles in protein quality control and can indirectly regulate transcription. Evidence suggests that RBR proteins are often parts of cullin-containing ubiquitin ligase complexes. The ubiquitin ligase Parkin is an RBR family protein whose mutations are involved in forms of familial Parkinson's disease.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1878416554  96 QRYRKLQFEKEVLLDPCRTWCPSSSCQAVCQLKEaDSARPQLVRCGNCTLEFCSACKASWHPGQEC 161
Cdd:pfam01485   1 EKYEKLLLKSYVESDPNLKWCPTPDCGYIIELTD-GCSNTSHVTCSKCGHEFCFNCKEEWHEGLTC 65

Metallo-peptidase family M12B Reprolysin-like; This zinc-binding metallo-peptidase has the characteriztic binding motif HExxGHxxGxxH of Reprolysin-like peptidases of family M12B.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 438 YLIELIDRVDDIYRNTSwddefkGYGVQIHQIIINKFPTQVDPGqlhynmegsprpkDNQVWDVKKLLEQFSSDIadNAS 517
Cdd:pfam13582   2 RIVSLVNRANTIYERDL------GIRLQLAAIIITTSADTPYTS-------------SDALEILDELQEVNDTRI--GQY 60

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 518 SVCLAHLFTYQDFDeGTLGLAYVassrdqalGGLCskpyypvPSVKKASYlntgltstkNYGKTILTKEADLVTTHELGH 597
Cdd:pfam13582  61 GYDLGHLFTGRDGG-GGGGIAYV--------GGVC-------NSGSKFGV---------NSGSGPVGDTGADTFAHEIGH 115

                  ....*..
gi 1878416554 598 NFGAEHD 604
Cdd:pfam13582 116 NFGLNHT 122

Rcat domain of ATP-dependent RNA helicase DEAH12 and similar proteins; This group includes Arabidopsis thaliana ATP-dependent RNA helicases DEAH11 and DEAH12, which may be bifunctional proteins that function as DEAD-box RNA helicases (EC 3.6.4.13) and RBR-type E3 ubiquitin-protein ligases (EC 2.3.2.31). As RNA helicases, they may utilize the energy from ATP hydrolysis to unwind RNA (or DNA). DEAD-box RNA helicases participate in every aspect of RNA metabolism. As E3 ubiquitin-protein ligase, they may function as part of E3 complexes, which accept ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfer it to substrates. Other members of this group may not have an RNA helicase domain. All members contain an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1878416554 188 IKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLE 222
Cdd:cd22585     2 VKRCPKCKSLIEKIDGCNHVTCTRCGTHICWVCLK 36

Rcat domain found in two RING fingers and DRIL [double RING finger linked] 1 (TRIAD1); TRIAD1, also called ariadne-2 (ARI-2), protein ariadne-2 homolog, Ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2), or UbcM4-interacting protein 48, is an RBR-type E3 ubiquitin-protein ligase that catalyzes the formation of polyubiquitin chains linked via lysine-48 as well as lysine-63 residues. Its auto-ubiquitylation can be catalyzed by the E2 conjugating enzyme UBCH7. TRIAD1 has been implicated in hematopoiesis, specifically in myelopoiesis, as well as in embryogenesis. It functions as a regulator of endosomal transport, and is required for the proper function of multivesicular bodies. It also acts as a novel ubiquitination target for proteasome-dependent degradation by murine double minute 2 (MDM2). As a proapoptotic protein, TRIAD1 promotes p53 activation, and inhibits MDM2-mediated p53 ubiquitination and degradation. Furthermore, TRIAD1 can inhibit the ubiquitination and proteasomal degradation of growth factor independence 1 (Gfi1), a transcriptional repressor essential for the function and development of many different hematopoietic lineages. TRIAD1 contains an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of TRIAD1 that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1878416554 189 KRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLES 223
Cdd:cd20360     4 KDCPKCHVCIEKNGGCNHMQCSKCKHEFCWMCLGD 38

Rcat domain found in cullin-9 (CUL-9) and similar proteins; CUL-9, also called UbcH7-associated protein 1 (H7-AP1), p53-associated parkin-like cytoplasmic protein, or PARC, is a cytoplasmic RBR-type E3 ubiquitin-protein ligase that function as a tumor suppressor and promotes p53-dependent apoptosis. It mediates the ubiquitination and degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. It is also a critical downstream effector of the 3M complex in the maintenance of microtubules and genome integrity. Moreover, CUL-9, together with CUL-7, forms homodimers and heterodimers, as well as some atypical cullin RING ligase complexes, which may exhibit ubiquitin ligase activity. CUL-9 contains a CPH domain (conserved in Cul7, PARC, and HERC2 proteins), a DOC (DOC1/APC10) domain, cullin homology domains linked with E3 ligase function, and a C-terminal RBR domain previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of CUL-9 that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1878416554 189 KRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLES 223
Cdd:cd20359     8 KRCPSCQAQIEKNEGCLHMTCAKCNHGFCWRCLKP 42

Zinc-dependent metalloprotease, salivary_gland_MPs. Metalloproteases secreted by the salivary glands of arthropods.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 415 LLLVADYRFYKHMGREEESTTlnYLIELIDRVDDIYRntswddEFKGYGVQ--IHQIIINKFPtQVDPGQlhynmegspR 492
Cdd:cd04272     5 LFVVVDYDHQSEFFSNEQLIR--YLAVMVNAANLRYR------DLKSPRIRllLVGITISKDP-DFEPYI---------H 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 493 PKDNQVWDVKKLLEQF-----SSDIADNASSVCLAHLFTYQDFDEG-----TLGLAYVassrdqalGGLCSKpyYPVPSV 562
Cdd:cd04272    67 PINYGYIDAAETLENFneyvkKKRDYFNPDVVFLVTGLDMSTYSGGslqtgTGGYAYV--------GGACTE--NRVAMG 136

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878416554 563 KKASYLNTGLtstknygktiltkeadLVTTHELGHNFGAEHD--------PDNIAYCAPSDEQGgkFVM-YpiaVSGDhP 633
Cdd:cd04272   137 EDTPGSYYGV----------------YTMTHELAHLLGAPHDgspppswvKGHPGSLDCPWDDG--YIMsY---VVNG-E 194

                         250       260
                  ....*....|....*....|....
gi 1878416554 634 NNKRFSNCSKASVSRTLKVKAPQC 657
Cdd:cd04272   195 RQYRFSQCSQRQIRNVFRRLGASC 218

Rcat domain found in an uncharacterized subfamily of RBR proteins; This subfamily contains uncharacterized members of the RBR family, including Arabidopsis thaliana mutator-like transposase and hypothetical protein At2g19610/F3P11.21. The RBR family of RING-type E3 ligases are characterized by containing a RBR domain, which was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. It is composed of an extended RING domain (RING1) followed by an in-between RING (IBR) domain and the catalytic domain, which is structurally an IBR domain but is commonly designated RING2. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently, where the IBR and RING2 domains have been renamed as BRcat and Rcat domains, respectively. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. RBR family members play roles in protein quality control and can indirectly regulate transcription. Evidence suggests that RBR proteins are often parts of cullin-containing ubiquitin ligase complexes. This model corresponds to the Rcat domain that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1878416554 189 KRCPKCKVYIERDEGCAQMMCKnCKHAFCWYC 220
Cdd:cd22584     3 RRCPQCGHMVELSEGCNHMTCR-CGYEFCYLC 33

RING finger, HC subclass, found in RING finger protein 14 (RNF14) and similar proteins; RNF14, also known as androgen receptor-associated protein 54 (ARA54), HFB30, or Triad2 protein, is an RBR-type E3 ubiquitin-protein ligase that is highly expressed in the testis and interacts with class III E2s (UBE2E2, UbcH6, and UBE2E3). Its differential localization may play an important role in testicular development and spermatogenesis in humans. RNF14 functions as a transcriptional regulator of mitochondrial and immune function in muscle. It is a ligand-dependent androgen receptor (AR) co-activator and may also may participate in enhancing cell cycle progression and cell proliferation via induction of cyclin D1. Moreover, RNF14 is crucial for colon cancer cell survival. It acts as a new enhancer of the Wnt-dependent transcriptional outputs that acts at the level of the T-cell factor/lymphoid enhancer factor (TCF/LEF)-beta-catenin complex. RNF14 contains an N-terminal RWD domain and a C-terminal RBR domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C3HC4-type RING-HC finger required for RBR-mediated ubiquitination.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1878416554  24 SCKLCLGEFPLEQMTTITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSACP 76
Cdd:cd16628     7 TCNICFLDKLGSECMYFKDCGHVYCKECLKEYFEVQIRDGNVTSLNCPEPKCA 59

Rcat domain found in parkin and similar proteins; Parkin, also called Parkinson juvenile disease protein 2, is an RBR-type E3 ubiquitin-protein ligase that is associated with recessive early onset Parkinson's disease (PD), and exerts a protective effect against dopamine-induced alpha-synuclein-dependent cell toxicity. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Parkin functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746, and AIMP2. It mediates monoubiquitination as well as Lys6-, Lys11-, Lys48- and Lys63-linked polyubiquitination of substrates depending on the context. Parkin may enhance cell viability and protects dopaminergic neurons from oxidative stress-mediated death by regulating mitochondrial function. It also limits the production of reactive oxygen species (ROS), and regulates cyclin-E during neuronal apoptosis. Moreover, parkin displays a ubiquitin ligase-independent function in transcriptional repression of p53. Parkin contains an N-terminal ubiquitin-like domain and a C-terminal RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the Rcat domain of parkin that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....
gi 1878416554 189 KRCPKCKVYIERDEGCAQMMC--KNCKHAFCWYC 220
Cdd:cd20357     8 KPCPKCKVPTEKNGGCMHMKCprPQCGLEWCWIC 41

BRcat (benign-catalytic) and Rcat (required-for-catalysis) domains, part of the RBR (RING1-BRcat-Rcat) domain; The RBR family of RING-type E3 ligases are characterized by containing an RBR (RING1-BRcat-Rcat) domain, which was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. It is composed of an extended RING domain (RING1) followed by an in-between RING (IBR) domain and the catalytic domain, which is structurally an IBR domain but is commonly designated as RING2. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBRs has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis), where the IBR and RING2 domains have been renamed as BRcat and Rcat domains, respectively. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. The BRcat domain adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity. RBR family members play roles in protein quality control and can indirectly regulate transcription. Evidence suggests that RBR proteins are often parts of cullin-containing ubiquitin ligase complexes.

                          10        20        30
                  ....*....|....*....|....*....|...
gi 1878416554 189 KRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCL 221
Cdd:cd14799     3 KWCPKCHFGFEKERGCMHATCPQCRQEFCWRCK 35

BRcat domain found in RING finger protein 19A (RNF19A); RNF19A, also called double ring-finger protein (Dorfin) or p38, is a transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligase that localizes to the ubiquitylated inclusions in Parkinson's disease (PD), dementia with Lewy bodies (LBs), multiple system atrophy, and amyotrophic lateral sclerosis (ALS). It interacts with Psmc3, a protein component of the 19S regulatory cap of the 26S proteasome, and further participates in the ubiquitin-proteasome system in acrosome biogenesis, spermatid head shaping, and development of the head-tail coupling apparatus and tail. It modulates the ubiquitination and degradation of Calcium-sensing receptor (CaR), which may contribute to a general mechanism for CaR quality control during biosynthesis. Moreover, RNF19A can also ubiquitylate mutant superoxide dismutase 1 (SOD1), the causative gene of familial ALS. It may associate with the endoplasmic reticulum-associated degradation (ERAD) pathway, which is related to the pathogenesis of neurodegenerative disorders, such as PD or Alzheimer's disease. It is also involved in the pathogenic process of PD and LB formation by ubiquitylation of synphilin-1. RNF19A contains an RBR domain followed by three TMs. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the BRcat domain of RNF19A that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1878416554  94 IMQRYRKLQFEKEVLLDPCRTWCPSSSC-QAVCQLKEADSARPQLVRCGnCTLEFCSACKASWHPGQEC 161
Cdd:cd20362     7 LMEKYEEFMLRRWLVADPDCRWCPAPDCgYAVIAFGCASCPKLTCGREG-CGTEFCYHCKQIWHPNQTC 74

RING finger, HC subclass, found in Saccharomyces cerevisiae translation termination inhibitor protein ITT1 and similar proteins; ITT1 is a protein that modulates the efficiency of translation termination, resulting in the readthrough of all three types of nonsense codons UAA, UAG and UGA. ITT1 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1878416554  25 CKLCLGEFPLEQMTtITQCQCVFCTLCLKQYVELLIKEGLETAISCPDSACPK 77
Cdd:cd23134     7 CGICFEEKKGSDFI-KLPCGHVFCRECLQDYYTIHIQEGEVSSVKCPDPNCGK 58

BRcat domain found in human homolog of Drosophila Ariadne (HHARI) and similar proteins; This subfamily includes Drosophila melanogaster protein ariadne-1 (ARI-1), and its eukaryotic homologs, such as HHARI. ARI-1 is a widely expressed Drosophila RING-finger protein that localizes mainly in the cytoplasm, and is required for neural development. It interacts with the ubiquitin-conjugating enzyme, UbcD10. HHARI is also called H7-AP2, monocyte protein 6 (MOP-6), protein ariadne-1 homolog, Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1), ariadne-1 (ARI-1), UbcH7-binding protein, UbcM4-interacting protein, or ubiquitin-conjugating enzyme E2-binding protein 1. It is an RBR-type E3 ubiquitin-protein ligase highly expressed in nuclei, where it is co-localized with nuclear bodies including Cajal, PML, and Lewy bodies. It interacts with the E2 conjugating enzymes UbcH7, UbcH8, UbcM4, and UbcD10 in human, mouse and fly, and modulates the ubiquitylation of substrate proteins including single-minded 2 (SIM2) and translation initiation factor 4E homologous protein (4EHP). It functions as a potent mediator of DNA damage-induced translation arrest, which protects stem and cancer cells against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. HHARI contains an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. This model corresponds to the BRcat domain of HHARI and similar proteins that adopt the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878416554  92 SDIMQRYRKLQFEKEVLLDPCRTWCPSSSCQAVCQLKEADsarPQLVRCgNCTLEFCSACKASWH 156
Cdd:cd20343     2 SKVRLKYQHLITNSFVECNRLLKWCPAPDCGHAVKVQYPD---ARPVTC-KCGHTFCFACGENWH 62