BRcat 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 functions 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 BRcat domain of CUL-9 that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767939561 2195 LLRGYVESCSNLTWCTNPQGCDRILCRQGLGCGTTCSKCGWASCFNCSFPEAHYPASCGHMSQWVDDGGYYDGM 2268
Cdd:cd20347     1 LLRGYVESCSNLTWCTNPQGCDRILCREGLGSGGTCSKCGWSSCFSCTFPEAHYPASCSHMSQWMDDGGYYEGM 74

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 767939561 2276 HLAKLISKRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKSWKPNHKDYYNCSAMVS 2333
Cdd:cd20359     1 HLAKLISKRCPSCQAQIEKNEGCLHMTCAKCNHGFCWRCLKPWKPTHKDYYNCSAMVS 58

Cullin family;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1595 SEQFARYIDQQIQGGLIGGAPGvemlgQLQRHLEPIMVL----SGLELattFEHFYQHYMADRLLSFGS----------S 1660
Cdd:pfam00888  353 PELLAKYIDDLLKKGLKGKSEE-----ELEEKLDKVITLfryiQDKDV---FEAFYKKHLAKRLLLGKSasddaersmiS 424

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1661 WLEGAVleqiGLCFPNRLpQLMLQSLSTSEELQRQFhlfqlqrldKLFLEQEDEeekrleeeeeeeeeeeaekelfiEDP 1740
Cdd:pfam00888  425 KLKEEC----GSEFTSKL-EGMFKDMELSKDLMKEF---------KEHLSENKS-----------------------SKK 467

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1741 SPAISILVLSPRCWPvsplcyLYHPRKC-LPTEFCDALDRFSSFYSQSQNHpvldmgphRRLQWTW-LGRAEL--QFGK- 1815
Cdd:pfam00888  468 GIDLSVNVLTSGAWP------TYLTSDFiLPPELEKAIERFEKFYLSKHSG--------RKLTWLHsLGTAELkaTFPKg 533

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 767939561  1816 --QILHVSTVQMWLLLKFNQT-EEVSVETLLKDSDLSPELLLQALVPLTSG 1863
Cdd:pfam00888  534 kkHELNVSTYQMAILLLFNDDgDSLSYEEIQEATGLPDEELKRTLQSLACA 584

BRcat 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 functions 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 BRcat domain of CUL-9 that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767939561 2195 LLRGYVESCSNLTWCTNPQGCDRILCRQGLGCGTTCSKCGWASCFNCSFPEAHYPASCGHMSQWVDDGGYYDGM 2268
Cdd:cd20347     1 LLRGYVESCSNLTWCTNPQGCDRILCREGLGSGGTCSKCGWSSCFSCTFPEAHYPASCSHMSQWMDDGGYYEGM 74

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 767939561 2276 HLAKLISKRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKSWKPNHKDYYNCSAMVS 2333
Cdd:cd20359     1 HLAKLISKRCPSCQAQIEKNEGCLHMTCAKCNHGFCWRCLKPWKPTHKDYYNCSAMVS 58

Cullin family;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1595 SEQFARYIDQQIQGGLIGGAPGvemlgQLQRHLEPIMVL----SGLELattFEHFYQHYMADRLLSFGS----------S 1660
Cdd:pfam00888  353 PELLAKYIDDLLKKGLKGKSEE-----ELEEKLDKVITLfryiQDKDV---FEAFYKKHLAKRLLLGKSasddaersmiS 424

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1661 WLEGAVleqiGLCFPNRLpQLMLQSLSTSEELQRQFhlfqlqrldKLFLEQEDEeekrleeeeeeeeeeeaekelfiEDP 1740
Cdd:pfam00888  425 KLKEEC----GSEFTSKL-EGMFKDMELSKDLMKEF---------KEHLSENKS-----------------------SKK 467

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1741 SPAISILVLSPRCWPvsplcyLYHPRKC-LPTEFCDALDRFSSFYSQSQNHpvldmgphRRLQWTW-LGRAEL--QFGK- 1815
Cdd:pfam00888  468 GIDLSVNVLTSGAWP------TYLTSDFiLPPELEKAIERFEKFYLSKHSG--------RKLTWLHsLGTAELkaTFPKg 533

                          250       260       270       280       290
                   ....*....|....*....|....*....|....*....|....*....|.
gi 767939561  1816 --QILHVSTVQMWLLLKFNQT-EEVSVETLLKDSDLSPELLLQALVPLTSG 1863
Cdd:pfam00888  534 kkHELNVSTYQMAILLLFNDDgDSLSYEEIQEATGLPDEELKRTLQSLACA 584

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 767939561  2190 KYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGCGT---TCSKCGWASCFNCSFPeAHYPASC 2252
Cdd:pfam01485    2 KYEKLLLKSYVESDPNLKWCPTP-DCGYIIELTDGCSNTshvTCSKCGHEFCFNCKEE-WHEGLTC 65

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
                   ....*....|....*....|....*....|....*....|....
gi 767939561  2283 KRCPS--CQAPIEKNEGC---LHMTCAKCNHGFCWRCLKSWKPN 2321
Cdd:pfam01485   19 KWCPTpdCGYIIELTDGCsntSHVTCSKCGHEFCFNCKEEWHEG 62

Anaphase-promoting complex, subunit 10 (APC10);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561  1185 LTDHNPKTYWESNGSTgSHYITLHMHRGVLVRQLTLLVASE-DSSYMPARVVVFGGDSTSCIgTELNTVNV-MPSA-SRV 1261
Cdd:pfam03256   45 LRDDNLDTYWQSDGSQ-PHLVNIQFRKKTPVKYVAIYLDYKlDESYTPSKISVRAGTGFNDL-QEVRVVDLeEPTGwVHI 122

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 767939561  1262 ILLENLNRFWPI--IQIRIKRCQQGGIDTRVRGVEVLGP 1298
Cdd:pfam03256  123 PLRDANGKPLRTfmLQIAVLSNHQNGRDTHVRQIKIYGP 161

APC10-like DOC1 domains of E3 ubiquitin ligases that mediate substrate ubiquitination; This model represens the APC10-like DOC1 domain of multi-domain proteins present in E3 ubiquitin ligases. E3 ubiquitin ligases mediate substrate ubiquitination (or ubiquitylation), a component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. APC10/DOC1 domains such as those present in HECT (Homologous to the E6-AP Carboxyl Terminus) and Cullin-RING (Really Interesting New Gene) E3 ubiquitin ligase proteins, HECTD3, and CUL7, respectively, are also included here. CUL7 is a member of the Cullin-RING ligase family and functions as a molecular scaffold assembling a SCF-ROC1-like E3 ubiquitin ligase complex consisting of Skp1, CUL7, Fbx29 F-box protein, and ROC1 (RING-box protein 1) and promotes ubiquitination. CUL7 is a multi-domain protein with a C-terminal cullin domain that binds ROC1 and a centrally positioned APC10/DOC1 domain. HECTD3 contains a C-terminal HECT domain which contains the active site for ubiquitin transfer onto substrates, and an N-terminal APC10/DOC1 domain which is responsible for substrate recognition and binding. An APC10/DOC1 domain homolog is also present in HERC2 (HECT domain and RLD2), a large multi-domain protein with three RCC1-like domains (RLDs), additional internal domains including zinc finger ZZ-type and Cyt-b5 (Cytochrome b5-like Heme/Steroid binding) domains, and a C-terminal HECT domain. Recent studies have shown that the protein complex HERC2-RNF8 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Also included in this hierarchy is an uncharacterized APC10/DOC1-like domain found in a multi-domain protein, which also contains CUB, zinc finger ZZ-type, and EF-hand domains. The APC10/DOC1 domain forms a beta-sandwich structure that is related in architecture to the galactose-binding domain-like fold; their sequences are quite dissimilar, however, and are not included here.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561 1167 DKCW-EKVEVSSNPHRASKLTDHNPKTYWESNGSTGSHYITLHMHRGVLVRQLTLLVASEDSSYMPARVVVFGGDSTSCI 1245
Cdd:cd08365     1 TKCYvESIEVSSNPADASRLTDGNTSTYWQSDGSQGSHWIRLKMKPDVLVRHLSLAVDATDSSYMPQRVVVAGGRSASNL 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 767939561 1246 gTELNTVNVMPS-ASRVILLENLNRFWPIIQIRIKRCQQGGIDTRVRGVEVL 1296
Cdd:cd08365    81 -QELRDVNIPPSvTGYVTLLEDATISQPYIEIRIKRCRSDGIDTRIHGLRIL 131

BRcat 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 functions 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 BRcat domain of CUL-9 that adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767939561 2195 LLRGYVESCSNLTWCTNPQGCDRILCRQGLGCGTTCSKCGWASCFNCSFPEAHYPASCGHMSQWVDDGGYYDGM 2268
Cdd:cd20347     1 LLRGYVESCSNLTWCTNPQGCDRILCREGLGSGGTCSKCGWSSCFSCTFPEAHYPASCSHMSQWMDDGGYYEGM 74

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 767939561 2276 HLAKLISKRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKSWKPNHKDYYNCSAMVS 2333
Cdd:cd20359     1 HLAKLISKRCPSCQAQIEKNEGCLHMTCAKCNHGFCWRCLKPWKPTHKDYYNCSAMVS 58

APC10-like DOC1 domain of HECTD3, a HECT E3 ubiquitin ligase protein that mediates substrate ubiquitination; This model represents the APC10/DOC1 domain present in HECTD3, a HECT (Homologous to the E6-AP Carboxyl Terminus) E3 ubiquitin ligase protein. HECT E3 ubiquitin ligases mediate substrate ubiquitination (or ubiquitylation), and are a component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. They also regulate the trafficking of many receptors, channels, transporters and viral proteins. HECTD3 (HECT domain-containing protein3) contains a C-terminal HECT domain with the active site for ubiquitin transfer onto substrates, and an N-terminal APC10/DOC1 domain, which is responsible for substrate recognition and binding. HECTD3 specifically recognizes the Trio-binding protein, Tara (Trio-associated repeat on actin), implicated in regulating actin cytoskeletal, cell motility and cell growth. Tara also binds to TRF1 and may participate in telomere maintenance and/or mitotic regulation through interacting with TRF1. HECTD3 interacts with and promotes the ubiquitination of Syntaxin 8, an endosomal syntaxin proposed to mediate distinct steps of endosomal protein trafficking. HECTD3-mediated Syntaxin 8 degradation has been suggested to contribute to the pathophysiology of neurodegenerative diseases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561 1171 EKVEVSS--NPHRASKLTDHNPKTYWESNGSTGSHYITLHMHRGVLVRQLTLLVASEDSSYMPARVVVFGGDSTSCigTE 1248
Cdd:cd08666     8 ESIEVSSytDDFNVSCLTDGDPDTYWESDGSQGQHWIRLHMKKGTIIKKLLLTVDATDDNYMPKRVAVYGGEGDNL--KK 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 767939561 1249 LNTVNV-MPSASRVILLENLNRFWPIIQIRIKRCQQGGIDTRVRGVEV 1295
Cdd:cd08666    86 LNDVSIdETLIGDVCILEDMTTHLPVIEIRIKECKDEGIDVRIRGIKI 133

RING finger, HC subclass, found in cullin-9 (CUL-9) and similar proteins; CUL-9, also known as UbcH7-associated protein 1 (H7-AP1), p53-associated parkin-like cytoplasmic protein, or PARC, is a cytoplasmic RBR-type E3 ubiquitin-protein ligase that is 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 (Cul7, PARC, and HERC2), a DOC (DOC1/APC10) domain, cullin homology (CH) 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 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 767939561 2117 DHCPVCVSPLGCDDDLPSLCCMHYCCKSCWNEYLTTRIEQNLVLNCTCPIADC 2169
Cdd:cd16624     1 THCPVCVSQLSPDEPLPTLCCMHYCCKSCWKEYLTTRIEQNLVLNCTCPITDC 53

Rcat (required-for-catalysis) domain, part of the RBR (RING1-BRcat-Rcat) domain; The RBR family of RING-type E3 ligases are characterized by containing an 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 changed to 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. The Rcat domain contains 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. This model corresponds to the Rcat domain that adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 767939561 2283 KRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKSW 2318
Cdd:cd20336     3 KKCPKCKVPIEKNGGCNHMTCSRCGTEFCWLCGKPW 38

Rcat 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. 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 Rcat domain of HHARI and similar proteins that are essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 767939561 2283 KRCPSCQAPIEKNEGCLHMTC--AKCNHGFCWRCLKSWKPNHKDYYNCSA 2330
Cdd:cd20356     7 KECPKCHVTIEKNGGCNHMVCrnQNCKYEFCWVCLGPWEPHGSSWYNCNR 56

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
                  ....*....|....*....|....*....|....*....|....*.
gi 767939561 2271 EAQSKHLAKLISKRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLK 2316
Cdd:cd20354     2 EKLSEEWLEKNSKPCPGCGTLIEKIDGCNKMTCTKCRTYFCWLCLK 47

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
                  ....*....|....*....|....*....|....*
gi 767939561 2283 KRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKS 2317
Cdd:cd20352     6 KRCPMCHVPIERDEGCAQMMCKNCKHVFCWYCLAS 40

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 767939561 2283 KRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLK 2316
Cdd:cd22585     3 KRCPKCKSLIEKIDGCNHVTCTRCGTHICWVCLK 36

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        40
                  ....*....|....*....|....*....|....*....|....*
gi 767939561 2279 KLISKRCPSCQAPIEKNEGCLHMTC--AKCNHGFCWRCLKSWKPN 2321
Cdd:cd20357     4 KKTTKPCPKCKVPTEKNGGCMHMKCprPQCGLEWCWICGCEWNRD 48

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 767939561  2190 KYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGCGT---TCSKCGWASCFNCSFPeAHYPASC 2252
Cdd:pfam01485    2 KYEKLLLKSYVESDPNLKWCPTP-DCGYIIELTDGCSNTshvTCSKCGHEFCFNCKEE-WHEGLTC 65

RING finger, HC subclass, found in two RING fingers and DRIL [double RING finger linked] 1 (TRIAD1); TRIAD1, also known as 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 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 767939561 2118 HCPVCVSPLGcDDDLPSLCCMHYCCKSCWNEYLTTRIEQNLVLNCTCPIADCPA 2171
Cdd:cd16773     2 TCGVCCEDVP-KDELFSLACGHYFCNDCWKQYLTVKIKDGVSTGIECMAPDCKV 54

Rcat 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 Rcat domain of RNF144B that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 767939561 2283 KRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKS 2317
Cdd:cd20369     7 KQCPVCRVYIERNEGCAQMMCKNCKHTFCWYCLQN 41

BRcat domain found in ankyrin repeat and IBR domain-containing protein 1 (ANKIB1) and similar proteins; ANKIB1 is an RBR-type E3 ubiquitin-protein ligase that may function as part of the E3 complex, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates. It contains N-terminal ankyrin repeats, and 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 ANKIB1 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 767939561 2196 LRGYVESCSNLTWCTNPqGCDR-ILCRQGLGCGTTCS---KCGWASCFNCSFpEAHYPASCGHMSQW 2258
Cdd:cd20346     1 LRSYVEDNPNLKWCPAP-GCGRaVELPGGGSEEGSPEvdcGCGHSFCFNCGE-EAHRPVDCETVKKW 65

Rcat domain found in E3 ubiquitin-protein ligase ARI1 and similar proteins; This subfamily contains probable RBR-type E3 ubiquitin-protein ligases (EC 2.3.2.31) including Arabidopsis thaliana ARI1, ARI2, and ARI3. They may function as part of E3 complexes, which accept ubiquitin from E2 ubiquitin-conjugating enzymes and then transfer it to substrates. Members of this subfamily 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 of ARI1-like proteins that are essential for RBR E3 ligase activity and adopt the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|...
gi 767939561 2282 SKRCPSCQAPIEKNEGCLHMTCaKCNHGFCWRC 2314
Cdd:cd22586     4 TKLCPKCSKPVEKNGGCNLVTC-RCGQHFCWLC 35

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
                   ....*....|....*....|....*....|....*....|....
gi 767939561  2283 KRCPS--CQAPIEKNEGC---LHMTCAKCNHGFCWRCLKSWKPN 2321
Cdd:pfam01485   19 KWCPTpdCGYIIELTDGCsntSHVTCSKCGHEFCFNCKEEWHEG 62

Rcat domain found in the RING finger protein 19 (RNF19) subfamily; This subfamily includes RING finger protein RNF19A and RNF19B, which are transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligases. RNF19A, also called double ring-finger protein (Dorfin) or p38, 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. RNF19B, also called IBR domain-containing protein 3, or natural killer (NK) lytic-associated molecule (NKLAM), plays a role in controlling tumor dissemination and metastasis. It is involved in the cytolytic function of NK cells and cytotoxic T lymphocytes (CTLs). It interacts with ubiquitin conjugates UbcH7 and UbcH8, and ubiquitinates uridine kinase like-1 protein, targeting it for degradation. RNF19B is a novel component of macrophage phagosomes and plays a role in macrophage anti-bacterial activity. It functions as a novel modulator of macrophage inducible nitric oxide synthase (iNOS) expression. Both RNF19A and RNF19B contain 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 Rcat domain of the RNF19 subfamily that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 767939561 2283 KRCPSCQAPIEK-NEG-CLHMTCAKCNHGFCWRCLK 2316
Cdd:cd20355     5 KPCPRCGALIIKmDDGsCNHMTCAVCGAEFCWLCMK 40

Cullin;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561   1642 FEHFYQHYMADRLLSFGS----------SWLEgavlEQIGLCFPNRLpQLMLQSLSTSEELQRQF-HLFQLQRLDKlfle 1710
Cdd:smart00182    8 FEKYYKKHLAKRLILNRSasddaeenmiTKLK----QECGYEFTSKL-ERMFRDISLSKDLNQSFkDMLENNPSAK---- 78

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939561   1711 qedeeekrleeeeeeeeeeeaekelfiedPSPAISILVLSPRCWPVSPLCYLYHprkcLPTEFCDALDRFSSFYSQSQNh 1790
Cdd:smart00182   79 -----------------------------PIIDLNVRVLTSGYWPTSSTEVEIN----LPQELEDALEEFEEFYLAKHS- 124

                           170       180
                    ....*....|....*....|....
gi 767939561   1791 pvldmgpHRRLQWTW-LGRAELQF 1813
Cdd:smart00182  125 -------GRKLTWLHsLGRGEVKA 141

RING finger, HC subclass, found in Arabidopsis thaliana protein ariadne homolog 6 (ARI6) and similar proteins; This subfamily includes ARI6 and ARI11. They might act as E3 ubiquitin-protein ligases, or as part of E3 complexes, which accept ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfer it to substrates. Members of this subfamily contain a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 767939561 2130 DDLPSLCCMHYCCKSCWNEYLTTRIEQNL-VLNCTCPIADCPA 2171
Cdd:cd23141    14 EEMRAASCGHYFCKTCWTGYIHTAISDGPgCLDLRCPDPSCPA 56

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 767939561 2119 CPVCVSplgcdDDLPSLC-----CMHYCCKSCWNEYLTTRIEQNLVLNCTCPIADCP 2170
Cdd:cd16628     8 CNICFL-----DKLGSECmyfkdCGHVYCKECLKEYFEVQIRDGNVTSLNCPEPKCA 59

RING finger, HC subclass, 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 a novel ubiquitin-conjugating enzyme, UbcD10. HHARI, also known as 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, 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 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 767939561 2119 CPVCVspLGCD-DDLPSLCCMHYCCKSCWNEYLTTRI-EQNLVLNCTCPIADC 2169
Cdd:cd16626     3 CDICY--LNYPnSYMTGLECGHKFCMQCWKEYLTTKImEEGMGQTISCPAHGC 53