APC10-like DOC1 domains in E3 ubiquitin ligases that mediate substrate ubiquitination; This family contains the single domain protein, APC10, a subunit of the anaphase-promoting complex (APC), as well as the 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. The APC, a multi-protein complex (or cyclosome), is a cell cycle-regulated, E3 ubiquitin ligase that controls important transitions in mitosis and the G1 phase by ubiquitinating regulatory proteins, thereby targeting them for degradation. APC10-like 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 in this hierarchy. 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 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 1958802201  942 DRCWEKVEVSSNPHRASKLTDRNPKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPARVVVFGGDSVGCIS 1021
Cdd:cd08665      1 DKCWEKVEVSSNPHRANKLTDGNPKTYWESNGSTGSHYINIHMHRGVVIRQLYMLVASEDSSYMPARVVVLGGDSPSCIT 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958802201 1022 TELNTVNVVPSASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVLG 1072
Cdd:cd08665     81 TELNAVNVSPTASRVVLLENMTRFWPIIQIRIKRCQQGGIDTRVRGLEILG 131

Mouse development and cellular proliferation protein Cullin-7; The Cullin Ring Ligase family member, Cul7, is required for normal mouse development and cellular proliferation. Cul7 has a CPH domain which is a p53 interaction domain. The CPH domain interaction surface of P53 is present in the tetramerization domain.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1958802201  149 RSEFSSRSGYGEYVQQTVQPGMRVRILDDYEEISAGDEGEFQQSNNGV---PPVQVFWQSTGRTYWVHWHMLEILGPE 223
Cdd:pfam11515    1 RSDFASRDDYAEYVRDNLAPGMRVRCCRDYEEVSAGDEGEVIQSNRGGlhdLNVQVDWQSKGRTYWVHWHHVEILGFP 78

RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1958802201 1872 DQCPVCISPLGPNDDSPSLCCLHCCCKSCWNEYLTTRIEQNFVLNCTCPIADC 1924
Cdd:cd16624      1 THCPVCVSQLSPDEPLPTLCCMHYCCKSCWKEYLTTRIEQNLVLNCTCPITDC 53

Cullin protein neddylation domain; This is the neddylation site of cullin proteins which are a family of structurally related proteins containing an evolutionarily conserved cullin domain. With the exception of APC2, each member of the cullin family is modified by Nedd8 and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chains. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex in Saccharomyces cerevisiae, and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle control and for embryogenesis in metazoans. The only identified Nedd8 substrates are cullins. Neddylation results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  1667 TLEQKRNLLSCLLVRILKAHGEkgLHIDQLVCLVLEAWQKGPNPpgrlgrsaavgvacSSTDVLSCILHLLGQGYVERRD 1746
Cdd:smart00884    1 VEEDRKLEIQAAIVRIMKSRKT--LSHSELVSEVIEQLKKRFKP--------------SVSDIKKRIESLIEREYLERDE 64

                    .
gi 1958802201  1747 D 1747
Cdd:smart00884   65 D 65

APC10-like DOC1 domain of CUL7, subunit of the SCF-ROC1-like E3 ubiquitin ligase complex that mediates substrate ubiquitination; This model represents the APC10/DOC1 domain present in CUL7, a subunit of the SCF-ROC1-like E3 Ubiquitin (Ub) ligase complex, which mediates substrate ubiquitination (or ubiquitylation), and is a component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. CUL7 is a member of the Cullin-RING ligase family and functions as a molecular scaffold assembling the SCF-ROC1-like E3 Ub ligase complex consisting of the adapter protein Skp1, CUL7, the WD40 repeat-containing F-box Fbw8 (also known as Fbx29), and ROC1 (RING-box protein 1). CUL7 is a large protein with a C-terminal cullin domain that binds ROC1 and additional domains, including an APC10/DOC1 domain. While the Fbw8 protein is responsible for substrate protein recognition, the ROC1 RING domain recruits an Ub-charged E2 Ub-conjugating enzyme for substrate ubiquitination. It remains to be determined how CUL7 binds to the Skp1-Fbw8 heterodimer. The CUL7 E3 Ub ligase has been implicated in the proteasomal degradation of the cellular proteins, cyclin D1, an important regulator of the G1 to S-phase cell cycle progression, and insulin receptor substrate 1, a critical component of the signaling pathways downstream of the insulin and insulin-like growth factor 1 receptor. CUL7 appears to be an important regulator of placental development. Germ line mutations of CUL7 are linked to 3-M syndrome and Yakuts short stature syndrome.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  942 DRCWEKVEVSSNPHRASKLTDRNPKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPARVVVFGGDSVGCIS 1021
Cdd:cd08665      1 DKCWEKVEVSSNPHRANKLTDGNPKTYWESNGSTGSHYINIHMHRGVVIRQLYMLVASEDSSYMPARVVVLGGDSPSCIT 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958802201 1022 TELNTVNVVPSASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVLG 1072
Cdd:cd08665     81 TELNAVNVSPTASRVVLLENMTRFWPIIQIRIKRCQQGGIDTRVRGLEILG 131

Mouse development and cellular proliferation protein Cullin-7; The Cullin Ring Ligase family member, Cul7, is required for normal mouse development and cellular proliferation. Cul7 has a CPH domain which is a p53 interaction domain. The CPH domain interaction surface of P53 is present in the tetramerization domain.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1958802201  149 RSEFSSRSGYGEYVQQTVQPGMRVRILDDYEEISAGDEGEFQQSNNGV---PPVQVFWQSTGRTYWVHWHMLEILGPE 223
Cdd:pfam11515    1 RSDFASRDDYAEYVRDNLAPGMRVRCCRDYEEVSAGDEGEVIQSNRGGlhdLNVQVDWQSKGRTYWVHWHHVEILGFP 78

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 1958802201 1872 DQCPVCISPLGPNDDSPSLCCLHCCCKSCWNEYLTTRIEQNFVLNCTCPIADC 1924
Cdd:cd16624      1 THCPVCVSQLSPDEPLPTLCCMHYCCKSCWKEYLTTRIEQNLVLNCTCPITDC 53

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 1958802201 1945 KYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGSGT---TCSKCGWASCFNCSFPeAHYPASC 2007
Cdd:pfam01485    2 KYEKLLLKSYVESDPNLKWCPTP-DCGYIIELTDGCSNTshvTCSKCGHEFCFNCKEE-WHEGLTC 65

Cullin, a subunit of E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1439 EQEEWKLERLEEEDRGQETGR-----------ELLTE---------DPGPAISVLVLSPRCWPVSPlcylHQPRKHLPTE 1498
Cdd:COG5647    483 QAELKMISMLKKVCGQEFTSKlegmfrdislsSEFTEafqhspqsyNKYLDLFVWVLTQAYWPLSP----EEVSIRLPKE 558

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1499 FCDALDGFSSFYShSEELGtgswrlrcipggrrgkaeatrqecqhypvldmgphRRLQWTW-LGRAEL--QFGDQTLH-- 1573
Cdd:COG5647    559 LVPILEGFKKFYS-SKHNG-----------------------------------RKLKWYWhLGSGEVkaRFNEGQKYle 602

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1574 ---VSTVQMWLLLNFNQTEEVSVEILLRNSGLSPELLHQALLPLTsdsgpltleEAQDFPQGGVLRLREP-----RSQTH 1645
Cdd:COG5647    603 istFSVYQLLVFLLFNDHEELTFEEILELTKLSTDDLKRVLQSLS---------CAKLVVLLKDDKLVSPntkfyVNENF 673

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1646 EEVLWLIP-PQTYLSVEKDEG----RTLEQKRNL-LSCLLVRILKAhgEKGLHIDQLVCLVLEAWQKGPNPpgrlgrsaa 1719
Cdd:COG5647    674 SSKLERIKiNYIAESECMQDNldthETVEEDRQAeLQACIVRIMKA--RKKLKHGDLVKEVIAQHKSRFEP--------- 742

                          330       340
                   ....*....|....*....|....*...
gi 1958802201 1720 vgvacSSTDVLSCILHLLGQGYVERRDD 1747
Cdd:COG5647    743 -----KVSMVKRAIETLIEKEYLERQAD 765

Cullin protein neddylation domain; This is the neddylation site of cullin proteins which are a family of structurally related proteins containing an evolutionarily conserved cullin domain. With the exception of APC2, each member of the cullin family is modified by Nedd8 and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chains. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex in Saccharomyces cerevisiae, and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle control and for embryogenesis in metazoans. The only identified Nedd8 substrates are cullins. Neddylation results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  1667 TLEQKRNLLSCLLVRILKAHGEkgLHIDQLVCLVLEAWQKGPNPpgrlgrsaavgvacSSTDVLSCILHLLGQGYVERRD 1746
Cdd:smart00884    1 VEEDRKLEIQAAIVRIMKSRKT--LSHSELVSEVIEQLKKRFKP--------------SVSDIKKRIESLIEREYLERDE 64

                    .
gi 1958802201  1747 D 1747
Cdd:smart00884   65 D 65

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

                            10        20        30
                    ....*....|....*....|....*....|....*...
gi 1958802201  2040 CPS--CQAPIEKNE--GCLHMTCARCNHGFCWRCLRSW 2073
Cdd:smart00647   21 CPApdCSAAIIVTEeeGCNRVTCPKCGFSFCFRCKVPW 58

APC10-like DOC1 domain of CUL7, subunit of the SCF-ROC1-like E3 ubiquitin ligase complex that mediates substrate ubiquitination; This model represents the APC10/DOC1 domain present in CUL7, a subunit of the SCF-ROC1-like E3 Ubiquitin (Ub) ligase complex, which mediates substrate ubiquitination (or ubiquitylation), and is a component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. CUL7 is a member of the Cullin-RING ligase family and functions as a molecular scaffold assembling the SCF-ROC1-like E3 Ub ligase complex consisting of the adapter protein Skp1, CUL7, the WD40 repeat-containing F-box Fbw8 (also known as Fbx29), and ROC1 (RING-box protein 1). CUL7 is a large protein with a C-terminal cullin domain that binds ROC1 and additional domains, including an APC10/DOC1 domain. While the Fbw8 protein is responsible for substrate protein recognition, the ROC1 RING domain recruits an Ub-charged E2 Ub-conjugating enzyme for substrate ubiquitination. It remains to be determined how CUL7 binds to the Skp1-Fbw8 heterodimer. The CUL7 E3 Ub ligase has been implicated in the proteasomal degradation of the cellular proteins, cyclin D1, an important regulator of the G1 to S-phase cell cycle progression, and insulin receptor substrate 1, a critical component of the signaling pathways downstream of the insulin and insulin-like growth factor 1 receptor. CUL7 appears to be an important regulator of placental development. Germ line mutations of CUL7 are linked to 3-M syndrome and Yakuts short stature syndrome.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  942 DRCWEKVEVSSNPHRASKLTDRNPKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPARVVVFGGDSVGCIS 1021
Cdd:cd08665      1 DKCWEKVEVSSNPHRANKLTDGNPKTYWESNGSTGSHYINIHMHRGVVIRQLYMLVASEDSSYMPARVVVLGGDSPSCIT 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958802201 1022 TELNTVNVVPSASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVLG 1072
Cdd:cd08665     81 TELNAVNVSPTASRVVLLENMTRFWPIIQIRIKRCQQGGIDTRVRGLEILG 131

APC10-like DOC1 domains in E3 ubiquitin ligases that mediate substrate ubiquitination; This family contains the single domain protein, APC10, a subunit of the anaphase-promoting complex (APC), as well as the 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. The APC, a multi-protein complex (or cyclosome), is a cell cycle-regulated, E3 ubiquitin ligase that controls important transitions in mitosis and the G1 phase by ubiquitinating regulatory proteins, thereby targeting them for degradation. APC10-like 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 in this hierarchy. 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 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 1958802201  943 RCW-EKVEVSSNPHRASKLTDRNPKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPARVVVFGGDSVGCIs 1021
Cdd:cd08159      1 KCYtASIEVSSNPLPVSRLTDGNYDTYWQSDGSQGSHWIRLFMKKDVLIRVLAIFVDMADSSYMPSLVVVYGGHSPSDL- 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1022 TELNTVNVVPSASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVL 1071
Cdd:cd08159     80 RELKDVNIRPSNGWVALLEDDTLKCPYIEIRIKRCRSDGIDTRIRGLRLL 129

Mouse development and cellular proliferation protein Cullin-7; The Cullin Ring Ligase family member, Cul7, is required for normal mouse development and cellular proliferation. Cul7 has a CPH domain which is a p53 interaction domain. The CPH domain interaction surface of P53 is present in the tetramerization domain.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1958802201  149 RSEFSSRSGYGEYVQQTVQPGMRVRILDDYEEISAGDEGEFQQSNNGV---PPVQVFWQSTGRTYWVHWHMLEILGPE 223
Cdd:pfam11515    1 RSDFASRDDYAEYVRDNLAPGMRVRCCRDYEEVSAGDEGEVIQSNRGGlhdLNVQVDWQSKGRTYWVHWHHVEILGFP 78

APC10-like DOC1 domain present in HERC2 (HECT domain and RLD2); This model represents the APC10/DOC1 domain present in HERC2 (HECT domain and RLD2), a large multi-domain protein with three RCC1-like domains (RLDs), additional internal domains including a zinc finger ZZ-type and Cyt-b5 (Cytochrome b5-like Heme/Steroid binding) domains, and a C-terminal HECT (Homologous to the E6-AP Carboxyl Terminus) domain. The APC10/DOC1 domain of HERC2 is a homolog of the APC10 subunit and the DOC1 domain present in E3 ubiquitin ligases which mediate substrate ubiquitination (or ubiquitylation), a component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. As suggested by structural relationships between HERC2 and other proteins such as HERC1, the proposed role for HERC2 in protein trafficking and degradation pathways is consistent with observations that mutations in HERC2 lead to neuromuscular secretory vesicle and sperm acrosome defects, other developmental abnormalities, and juvenile lethality of jdf2 mice. Recent studies have shown that the protein complex, HERC2-RNF8, coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  929 RHLCQGSSVEVKE-DRCWEKVEVSSNPHRASKLTDRNpKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPA 1007
Cdd:cd08664     11 PELNAGEGDLIDDwSRCVRSLTVSSNENQAKRLIDGS-GSYWQSSGSQGKHWIRLELHPDVLIHSLKIIVDPADSSYMPS 89

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1958802201 1008 RVVVFGGDSVGCIsTELNTVNVVPSASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVL 1071
Cdd:cd08664     90 LVVVSGGDSLNSL-KELKTINVNATDTLVTLLQDVKEYYRYIEIAIKQCRNNGIDCKIHGLNII 152

APC10/DOC1-like domain of uncharacterized Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1) and homologs; This model represents the APC10/DOC1-like domain present in the uncharacterized Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1) of Mus musculus. Members of this family contain EF-hand, APC10, CUB, and zinc finger ZZ-type domains. ZZEF1-like APC10 domains are homologous to the APC10 subunit/DOC1 domains present in E3 ubiquitin ligases, which mediate substrate ubiquitination (or ubiquitylation), and are components of the ubiquitin-26S proteasome pathway for selective proteolytic degradation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  943 RCWEKVEVSSNPHRASKLTDRNPKTYWESNGSTGSHSITLHMHRGVLIRQLTLLVASEDSSYMPARVVVfggdSVGCIST 1022
Cdd:cd08667      2 KCYAYIEVSSNSADIDRMTDGETSTYWQSDGSARSHWIRLKMKPDVVLRHLSIAVAATDQSYMPQQVTV----SVGRSAS 77

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1958802201 1023 ELNTVNVV--PS--ASRVTLLENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVLG 1072
Cdd:cd08667     78 SLQEVRDVhiPSnvTGYVTLLENANISYLVVQINIKRCHSDGCDTRIHGLKTIG 131

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 1958802201 2038 KRCPSCQAPIEKNEGCLHMTCARCNHGFCWRCLRSW 2073
Cdd:cd20336      3 KKCPKCKVPIEKNGGCNHMTCSRCGTEFCWLCGKPW 38

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 1958802201 1872 DQCPVCISPLGPNDDSPSLCCLHCCCKSCWNEYLTTRIEQNFVLNCTCPIADC 1924
Cdd:cd16624      1 THCPVCVSQLSPDEPLPTLCCMHYCCKSCWKEYLTTRIEQNLVLNCTCPITDC 53

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 1958802201 2038 KRCPSCQAPIEKNEGCLHMTC--ARCNHGFCWRCLRSWKPSHKDYYNCSA 2085
Cdd:cd20356      7 KECPKCHVTIEKNGGCNHMVCrnQNCKYEFCWVCLGPWEPHGSSWYNCNR 56

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 1958802201 2038 KRCPSCQAPIEKNEGCLHMTCARCNHGFCWRCLRS 2072
Cdd:cd20352      6 KRCPMCHVPIERDEGCAQMMCKNCKHVFCWYCLAS 40

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1958802201  1945 KYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGSGT--TCSKCGWASCFNCSFPeAHYPASC 2007
Cdd:smart00647    2 KYERLLLESYVESNPDLKWCPAP-DCSAAIIVTEEEGCNrvTCPKCGFSFCFRCKVP-WHSPVSC 64

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 1958802201 1945 KYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGSGT---TCSKCGWASCFNCSFPeAHYPASC 2007
Cdd:pfam01485    2 KYEKLLLKSYVESDPNLKWCPTP-DCGYIIELTDGCSNTshvTCSKCGHEFCFNCKEE-WHEGLTC 65

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        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958802201 1939 SPEVISKYEKALLRGYVESCSNLTWCTNPqGCDRILCRQGLGS-GTTCsKCGWASCFNCSfPEAHYPASCGHMSQWV 2014
Cdd:cd20343      1 DSKVRLKYQHLITNSFVECNRLLKWCPAP-DCGHAVKVQYPDArPVTC-KCGHTFCFACG-ENWHEPVKCRLLKKWI 74

Rcat domain found in RING finger protein 217 (RNF217); RNF217, also called IBR domain-containing protein 1 (IBRDC1), is a transmembrane (TM) domain-containing RBR-type E3 ubiquitin-protein ligase, with different splice variants, that is mainly expressed in testis and skeletal muscle. It interacts with the anti-apoptotic protein HAX1, and is adjacent to a translocation breakpoint involving ETV6 in childhood acute lymphoblastic leukemia (ALL). RNF217 contains an RBR domain followed by 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 RNF217 that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                           10        20        30
                   ....*....|....*....|....*....|..
gi 1958802201 2038 KRCPSCQAPIEKNEGCLHMTCARCNHGFCWRC 2069
Cdd:cd20350      6 QKCPKCKVYIQRSEGCDHMTCSQCNTNFCYRC 37

APC10 subunit of the anaphase-promoting complex (APC) that mediates substrate ubiquitination; This model represents the single domain protein APC10, a subunit of the anaphase-promoting complex (APC), which is a multi-subunit E3 ubiquitin ligase. E3 ubiquitin ligases mediate substrate ubiquitination (or ubiquitylation), a vital component of the ubiquitin-26S proteasome pathway for selective proteolytic degradation. The APC (also known as the cyclosome), is a cell cycle-regulated E3 ubiquitin ligase that controls important transitions in mitosis and the G1 phase by ubiquitinating regulatory proteins, thereby targeting them for degradation. In mitosis, the APC initiates sister chromatid separation by ubiquitinating the anaphase inhibitor securin and triggers exit from mitosis by ubiquitinating cyclin B. The C-terminus of APC10 binds to CDC27/APC3, an APC subunit that contains multiple tetratrico peptide repeats. APC10 domains are homologous to the DOC1 domains present in the HECT (Homologous to the E6-AP Carboxyl Terminus) E3 ubiquitin ligase protein, and the Cullin-RING (Really Interesting New Gene) E3 ubiquitin ligase complex. 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 1958802201  960 LTDRNPKTYWESNGSTgSHSITLHMHRGVLIRQLTLLVA-SEDSSYMPARVVVFGGDSVGCIsTELNTVNVV-PSA-SRV 1036
Cdd:cd08366     23 LRDDSLDTYWQSDGPQ-PHLINIQFSKKTDISAVALYLDyKLDESYTPSKISIRAGTSPHDL-QEVRTVELEePNGwVHI 100

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1958802201 1037 TLLENLSRfWPI----IQIRIKRCQQGGIDTRVRGVEVLG 1072
Cdd:cd08366    101 PLEDNRDG-KPLrtffLQIAILSNHQNGRDTHIRQIKVYG 139

Cullin family;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1368 FEHFYQYYMADRLLsLG---SSWLEGAVL----EQIGLCFPNRLpQLMLQSLRTSEELQRGFllfqlqqldrqlleqgeq 1440
Cdd:pfam00888  396 FEAFYKKHLAKRLL-LGksaSDDAERSMIsklkEECGSEFTSKL-EGMFKDMELSKDLMKEF------------------ 455

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1441 eewklerleeedrgQETGRELLTEDPGPAISVLVLSPRCWPVSPlcylhQPRKHLPTEFCDALDGFSSFYS--HSeelgt 1518
Cdd:pfam00888  456 --------------KEHLSENKSSKKGIDLSVNVLTSGAWPTYL-----TSDFILPPELEKAIERFEKFYLskHS----- 511

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201 1519 gswrlrcipggrrgkaeatrqecqhypvldmgpHRRLQWTW-LGRAEL--QFGDQT---LHVSTVQMWLLLNFNQT-EEV 1591
Cdd:pfam00888  512 ---------------------------------GRKLTWLHsLGTAELkaTFPKGKkheLNVSTYQMAILLLFNDDgDSL 558

                          250       260
                   ....*....|....*....|....
gi 1958802201 1592 SVEILLRNSGLSPELLHQALLPLT 1615
Cdd:pfam00888  559 SYEEIQEATGLPDEELKRTLQSLA 582

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 1958802201 2038 KRCPSCQAPIEKNEGCLHMTCARCNHGFCWRCLR 2071
Cdd:cd14799      3 KWCPKCHFGFEKERGCMHATCPQCRQEFCWRCKR 36

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 1958802201 2038 KRCPS--CQAPIEKNEGC---LHMTCARCNHGFCWRCLRSW 2073
Cdd:pfam01485   19 KWCPTpdCGYIIELTDGCsntSHVTCSKCGHEFCFNCKEEW 59

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 1958802201 2038 KRCPSCQAPIEK-NEG-CLHMTCARCNHGFCWRCLR 2071
Cdd:cd20355      5 KPCPRCGALIIKmDDGsCNHMTCAVCGAEFCWLCMK 40

Anaphase-promoting complex, subunit 10 (APC10);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  960 LTDRNPKTYWESNGSTgSHSITLHMHRGVLIRQLTLLVASE-DSSYMPARVVVFGGDSVGCIsTELNTVNVV-PSA-SRV 1036
Cdd:pfam03256   45 LRDDNLDTYWQSDGSQ-PHLVNIQFRKKTPVKYVAIYLDYKlDESYTPSKISVRAGTGFNDL-QEVRVVDLEePTGwVHI 122

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1958802201 1037 TLLENLSRFWPI--IQIRIKRCQQGGIDTRVRGVEVLGP 1073
Cdd:pfam03256  123 PLRDANGKPLRTfmLQIAVLSNHQNGRDTHVRQIKIYGP 161

Rcat domain found in HOIL-1-interacting protein (HOIP) and similar proteins; HOIP, also called RING finger protein 31 (RNF31) or zinc in-between-RING-finger ubiquitin-associated domain protein, together with HOIL-1 and SHARPIN, forms the E3-ligase complex (also known as linear-ubiquitin-chain assembly complex LUBAC) that regulates NF-kappaB activity and apoptosis. It also interacts with the atypical mammalian orphan receptor DAX-1, trigger DAX-1 ubiquitination and stabilization, and participate in repressing steroidogenic gene expression. HOIP contains three Npl4 zinc fingers, a central ubiquitin-associated (UBA) domain responsible for the interaction with the N-terminal ubiquitin-like domain (UBL) of HOIL-1L, an RBR domain, and a C-terminal linear chain determining domain (LDD). 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 HOIP that is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1958802201 2026 EAQSKHLAKLISKR---CPSCQAPIEKNEG-CLHMTCARCNHGFCWRCLRSWKPSHK 2078
Cdd:cd20351      2 EYQAQGLAAYLAENgidCPKCKFRYALAKGgCMHFTCTQCRHEFCSGCYNPFKAGNK 58

Anaphase-promoting complex (APC), subunit 10 [Cell division and chromosome partitioning / Posttranslational modification, protein turnover, chaperones];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958802201  960 LTDRNPKTYWESNGSTgSHSITLHMHRGVLIRQLTLLVA-SEDSSYMPARVVVFGGDSVGCIStELNTVNVVPSASRVTL 1038
Cdd:COG5156     46 LLDDNMDTYWQSDGVQ-PHSIQISFDKRRYIQSVQLFLSfTQDESYTPSKIGVRAGLTREDVR-EISSVEVVEPEGWVTL 123

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1958802201 1039 -----LENLSRFWPIIQIRIKRCQQGGIDTRVRGVEVLGP 1073
Cdd:COG5156    124 svadkREDDLLKCIYILVVINSNHQEGKDSHVRHIKIYEP 163

BRcat (benign-catalytic) 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 as 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 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. The model corresponds to the BRcat domain.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 1958802201 2038 KRCPS--CQAPI--EKNEGCLHMTCARCNHGFCWRCLRSW 2073
Cdd:cd20335      5 RWCPTpdCGGVIrvEEPGDGPRVTCPSCGTSFCFKCKEEW 44