MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  796 RDSHNAKDNPKSKEKESENVPGDGKGNKHKKHRKRRKGEESESFLNPELLETSRKCRESSGIDETKTDTlfvlpsrddat 875
Cdd:PTZ00121 1243 KKAEEERNNEEIRKFEEARMAHFARRQAAIKAEEARKADELKKAEEKKKADEAKKAEEKKKADEAKKKA----------- 1311

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  876 pvrDEPMDAESITFKSVSDKDKREKDKPKVKSDKTKRKSDGSATAKKDNVLKPSKGPQEKVDGDREKSPRSEPPLKKAKE 955
Cdd:PTZ00121 1312 ---EEAKKADEAKKKAEEAKKKADAAKKKAEEAKKAAEAAKAEAEAAADEAEAAEEKAEAAEKKKEEAKKKADAAKKKAE 1388

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  956 EATKIDSVKPSSSSQKdEKVTGTPRKAHSKsaKEHQEAKPAKDEKVKKDCSKDiKSEKPASKDEKAKKPEKNKlldsKGE 1035
Cdd:PTZ00121 1389 EKKKADEAKKKAEEDK-KKADELKKAAAAK--KKADEAKKKAEEKKKADEAKK-KAEEAKKADEAKKKAEEAK----KAE 1460

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1036 KRKRKTEEKSVDKDFESSSMKISKVEGTEIVKPSPKRKmegdVEKLERTPEKDKIASSTTPAKKIKlNRETGKKIGNAEN 1115
Cdd:PTZ00121 1461 EAKKKAEEAKKADEAKKKAEEAKKADEAKKKAEEAKKK----ADEAKKAAEAKKKADEAKKAEEAK-KADEAKKAEEAKK 1535

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1116 ASTTKEPSEKLESTSSKIKQEKVKGKAKRKVAGSegssstlvdytstsstggspvRKSEEKtdtKRTVIKTMEEYNNDNT 1195
Cdd:PTZ00121 1536 ADEAKKAEEKKKADELKKAEELKKAEEKKKAEEA---------------------KKAEED---KNMALRKAEEAKKAEE 1591

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1196 APAEDVIIMIQVPQSKWDKDDFESEEEDVKTTQpiqsvgkpssiIKNVTTKPSATAKYTEKESEQPEKLQKLPKEASHEL 1275
Cdd:PTZ00121 1592 ARIEEVMKLYEEEKKMKAEEAKKAEEAKIKAEE-----------LKKAEEEKKKVEQLKKKEAEEKKKAEELKKAEEENK 1660

                         490       500       510       520       530       540       550       560
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1276 MQHELRSSKgsASSEKGRAKDrehsgSEKDNPDKRKSGAQPDKESTVDRLSEQghfktlsQSSKETRTSEKHESVRGSSN 1355
Cdd:PTZ00121 1661 IKAAEEAKK--AEEDKKKAEE-----AKKAEEDEKKAAEALKKEAEEAKKAEE-------LKKKEAEEKKKAEELKKAEE 1726

                         570       580       590       600       610       620       630       640
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1356 KdftpgRDKKVDYDSRDYSSSKRRDE--RGELARRKDSPPRGKESLSGQKSKLREERDLPKKGAESKKSNSSPPRDKKPH 1433
Cdd:PTZ00121 1727 E-----NKIKAEEAKKEAEEDKKKAEeaKKDEEEKKKIAHLKKEEEKKAEEIRKEKEAVIEEELDEEDEKRRMEVDKKIK 1801

                  ....*..
gi 148685338 1434 DHKAPYE 1440
Cdd:PTZ00121 1802 DIFDNFA 1808

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 148685338  145 PDELLCLICKDIMTDAVVIPCCGNSYCDECIRTALLESDeHTCPTCHQNDVSPDAL 200
Cdd:cd16620     1 PDELKCPICKDLMKDAVLTPCCGNSFCDECIRTALLEED-FTCPTCKEPDVSPDAL 55

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|.
gi 148685338    150 CLICKDIMTDAVVIPCCGNSYCDECIRTaLLESDEHTCPTC 190
Cdd:smart00184    1 CPICLEEYLKDPVILPCGHTFCRSCIRK-WLESGNNTCPIC 40

cell wall-binding protein EntB; This HMM describes the cell wall-binding protein EntB, as found in Bacillus cereus. EntB is related to EntA, EntC, and EndD. All Ent family proteins have a signal peptide, an N-terminal SH3 domain and a C-terminal 3D (Asp-Asp-Asp) domain. EntB and EndC have a central region with a highly variable number of repeats resembling KAXEXX. The gene symbol derives from the notion that at least some members of the family function as enterotoxins, but more recent descriptions focus on roles in stress response and cell wall integrity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  895 KDKREKDKPKVKSDKTKRKSDGSATAKKDNVLKPSKGPQEKVDGDREKSPRSEPPLK---KAKEEATKIDSVKPSSSS-- 969
Cdd:NF040676  166 KAKEEAKTQKVAKAKETTKAQEIVKPKEEVKVQEVVKPKEEPKVQEIVKPKEEVKVQeevKPKEEEKVQEIVKPKEEAkv 245

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  970 QKDEKVTGTPRKAHSKSAKEHQEAKPAKDEKVKKDCSKDIKSEKPASKDEKAKKPEKNKLLDSKGEKRKRKTEEKSVDKD 1049
Cdd:NF040676  246 QEEVKVKEEAKVQEIAKAKEEAKAQEIAKAKEEAKAQEIAKAKEEAKAQEIAKAKEEEKAQEIAKAKEEAKAREIAKAKE 325

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 148685338 1050 fESSSMKISKVEGTEIVKPSPKRKMEGDVEKLERTPEKDKIASSTtpakkiKLNRETGKKIGNAENASTTKEPSE 1124
Cdd:NF040676  326 -EEKAREIAKAKEEAKAREIAKAKEEAKAREIAKAKEEERAKEAS------KNNIQSAKRELTVVATAYTADPSE 393

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 148685338  145 PDELLCLICKDIMTDAVVIPCCGNSYCDECIRTALLESDeHTCPTCHQNDVSPDAL 200
Cdd:cd16620     1 PDELKCPICKDLMKDAVLTPCCGNSFCDECIRTALLEED-FTCPTCKEPDVSPDAL 55

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  834 EESESFLNPELLETSRKCRESSGIDETKTdtlfVLPSRDDATPVR--DEPMDAESITFKSVSDKDKREKDKPKVKSDKtK 911
Cdd:PTZ00121 1203 EAARKAEEERKAEEARKAEDAKKAEAVKK----AEEAKKDAEEAKkaEEERNNEEIRKFEEARMAHFARRQAAIKAEE-A 1277

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  912 RKSDGSATAKKDNVLKPSKGPQEKVDGDR-----EKSPRSEPPLKKAKEEATKIDSVKPSSSSQKdekvtgtpRKAHSKS 986
Cdd:PTZ00121 1278 RKADELKKAEEKKKADEAKKAEEKKKADEakkkaEEAKKADEAKKKAEEAKKKADAAKKKAEEAK--------KAAEAAK 1349

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  987 AKEHQEAKPAKDEKVKKDCSKDIKSEKPASKDEKAKKPEKNKlldsKGEKRKRKTEEKSVDKDfesssmKISKVEGTEIV 1066
Cdd:PTZ00121 1350 AEAEAAADEAEAAEEKAEAAEKKKEEAKKKADAAKKKAEEKK----KADEAKKKAEEDKKKAD------ELKKAAAAKKK 1419

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1067 KPSPKRKmegdVEKLERTPEKDKIASSTTPAKKIKLNRETGKKignAENASTTKEPSEKLESTSSKIKQEKVKGKAKRKV 1146
Cdd:PTZ00121 1420 ADEAKKK----AEEKKKADEAKKKAEEAKKADEAKKKAEEAKK---AEEAKKKAEEAKKADEAKKKAEEAKKADEAKKKA 1492

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1147 AGSEGSSSTLvdytstsstggspvRKSEEKTDTKRTVIKTMEEYNNDNTAPAEDviimiqvpqsKWDKDDFESEEEDVKT 1226
Cdd:PTZ00121 1493 EEAKKKADEA--------------KKAAEAKKKADEAKKAEEAKKADEAKKAEE----------AKKADEAKKAEEKKKA 1548

                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1227 TQpiqsVGKPSSIIKNVTTKPSATAKYTEKESE----QPEKLQKLPKEASHELMQHELRSSKGSASSEKGRAKDREHSGS 1302
Cdd:PTZ00121 1549 DE----LKKAEELKKAEEKKKAEEAKKAEEDKNmalrKAEEAKKAEEARIEEVMKLYEEEKKMKAEEAKKAEEAKIKAEE 1624

                         490       500       510       520       530       540       550       560
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1303 EKDNPDKRKSGAQPDKESTVDRlseqghfktlsQSSKETRTSEKHESVRGSSNKdftpgrdKKVDYDSRDYSSSKRRDER 1382
Cdd:PTZ00121 1625 LKKAEEEKKKVEQLKKKEAEEK-----------KKAEELKKAEEENKIKAAEEA-------KKAEEDKKKAEEAKKAEED 1686

                         570       580       590       600       610       620       630       640
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1383 gelARRKDSPPRGKESLSGQKSKLREERDLPKKGAESKKSNSSPPRDKKPHDHKAPYETKRPCEETKPVDKNSGK----- 1457
Cdd:PTZ00121 1687 ---EKKAAEALKKEAEEAKKAEELKKKEAEEKKKAEELKKAEEENKIKAEEAKKEAEEDKKKAEEAKKDEEEKKKiahlk 1763

                         650
                  ....*....|....*.
gi 148685338 1458 -EREKHAAEARNGKES 1472
Cdd:PTZ00121 1764 kEEEKKAEEIRKEKEA 1779

HC subclass of RING (RING-HC) finger and its variants; 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 a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in 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 enables efficient transfer of ubiquitin from E2 to the substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 148685338  148 LLCLICKDIMTDAVVIPcCGNSYCDECIRTaLLESDEHTCPTC 190
Cdd:cd16449     1 LECPICLERLKDPVLLP-CGHVFCRECIRR-LLESGSIKCPIC 41

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 148685338  144 IPDELLCLICKDIMTDAVVIpCCGNSYCDECIRTALLESDEHTCPTCHQNdVSPDALIANKFLRQAV 210
Cdd:cd16599     1 FKEELLCPICYEPFREAVTL-RCGHNFCKGCVSRSWERQPRAPCPVCKEA-SSSDDLRTNHTLNNLV 65

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 148685338  146 DELLCLICKDIMTDAVVIPcCGNSYCDECIRTAL--LESDEHTCPTC 190
Cdd:cd16597     4 EELTCSICLELFKDPVTLP-CGHNFCGVCIEKTWdsQHGSEYSCPQC 49

RING finger, HC subclass, found in postreplication repair protein RAD18 and similar proteins; RAD18, also known as HR18 or RING finger protein 73 (RNF73), is an E3 ubiquitin-protein ligase involved in post replication repair of UV-damaged DNA via its recruitment to stalled replication forks. It associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on K164. It also interacts with another E2 ubiquitin conjugating enzyme RAD6 to form a complex that monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Moreover, Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins. It can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after ionizing radiation (IR) exposure. RAD18 contains a C3HC4-type RING-HC finger, a ubiquitin-binding zinc finger domain (UBZ), a SAP (SAF-A/B, Acinus and PIAS) domain, and a RAD6-binding domain (R6BD).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 148685338  146 DELL-CLICKDIMTDAVVIPCCGNSYCDECIRTALleSDEHTCPTCHQNDVSPD 198
Cdd:cd16529     2 DDLLrCPICFEYFNTAMMITQCSHNYCSLCIRRFL--SYKTQCPTCRAAVTESD 53

RING finger, HC subclass, found in tripartite motif-containing protein 62 (TRIM62) and similar proteins; TRIM62, also known as Ductal Epithelium Associated Ring Chromosome 1 (DEAR1), is a cytoplasmic E3 ubiquitin-protein ligase that was identified as a dominant regulator of acinar morphogenesis in the mammary gland. It is implicated in the inflammatory response of immune cells by regulating the Toll-like receptor 4 (TLR4) signaling pathway, leading to increased activity of the activator protein 1 (AP-1) transcription factor in primary macrophages. It is also involved in muscular protein homeostasis, especially during inflammation-induced atrophy, and may play a role in the pathogenesis of ICU-acquired weakness (ICUAW) by activating and maintaining inflammation in myocytes. Moreover, TRIM62 facilitates K27-linked poly-ubiquitination of CARD9 and also regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. It also functions as a chromosome 1p35 tumor suppressor and negatively regulates transforming growth factor beta (TGFbeta)-driven epithelial-mesenchymal transition (EMT) by binding to and promoting the ubiquitination of SMAD3, a major effector of TGFbeta-mediated EMT. TRIM62 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 148685338  146 DELLCLICKDIMTDAVVIPcCGNSYCDECIRTALLESDEHTCPTCHQ 192
Cdd:cd16608     5 DELLCSICLSIYQDPVSLG-CEHYFCRQCITEHWSRSEHRDCPECRR 50

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 148685338  146 DELLCLICKDIMTDAVVIPcCGNSYCDECIRTALLESDEHT--CPTCHQN 193
Cdd:cd16609     2 EELTCSICLGLYQDPVTLP-CQHSFCRACIEDHWRQKDEGSfsCPECRAP 50

Zinc finger, C3HC4 type (RING finger);

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 148685338   146 DELLCLICKDIMTDAVVIPCCGNSYCDECIRTalLESDEHTCPTCHQN 193
Cdd:pfam13920    1 EDLLCVICLDRPRNVVLLPCGHLCLCEECAER--LLRKKKKCPICRQP 46

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, closely related tripartite motif-containing proteins, belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 148685338  146 DELLCLICKDIMTDAVVIPCcGNSYCDECIRTALLESDE-HTCPTCHQN 193
Cdd:cd16594     4 EELTCPICLDYFTDPVTLDC-GHSFCRACIARCWEEPETsASCPQCRET 51

Modified RING finger, HC subclass (C4C4-type), found in tripartite motif-containing protein 37 (TRIM37) and similar proteins; TRIM37, also known as mulibrey nanism protein, or MUL, is a peroxisomal E3 ubiquitin-protein ligase that is involved in the tumorigenesis of several cancer types, including pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer, and sporadic fibrothecoma. It mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. Moreover, TRIM37 possesses anti-HIV-1 activity, and interferes with viral DNA synthesis. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction, and hepatomegaly. TRIM37 belongs to the C-VIII subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a MATH (meprin and TRAF-C homology) domain positioned C-terminal to the RBCC domain. Its MATH domain has been shown to interact with the TRAF (TNF-Receptor-Associated Factor) domain of six known TRAFs in vitro.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 148685338  148 LLCLICKDIMTDAVVIPCCGNSYCDECIRTALLESdEHTCPTC 190
Cdd:cd16619     1 FRCFICMEKLRDPRLCPHCSKLFCKGCIRRWLSEQ-RSSCPHC 42

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 148685338  150 CLICKDIMTDAVVIPCcGNSYCDECIRTAlLESDEHTCPTC 190
Cdd:cd16509     6 CAICLDSLTNPVITPC-AHVFCRRCICEV-IQREKAKCPMC 44

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  801 AKDNPKSKEKESENVPGDGKGNKHKKHRKRRKGEESESFLNPELLETSRKCRESSGIDET-KTDTLFVLPSRDDATPVRD 879
Cdd:PTZ00121 1492 AEEAKKKADEAKKAAEAKKKADEAKKAEEAKKADEAKKAEEAKKADEAKKAEEKKKADELkKAEELKKAEEKKKAEEAKK 1571

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  880 EPMD----------AESITFKSVSDKDKREKDKPKVKSDKTKRKSDGSATAKKDNVLKPSKGPQEKVDGDREKSPRSEPP 949
Cdd:PTZ00121 1572 AEEDknmalrkaeeAKKAEEARIEEVMKLYEEEKKMKAEEAKKAEEAKIKAEELKKAEEEKKKVEQLKKKEAEEKKKAEE 1651

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338  950 LKKAkEEATKIDSVKPSSSSQKDEKVTGTPRKAHSKSAKEHQEAKPAKDEKVKKDCSKDIKSEKPASKDEKAKKPEKNKL 1029
Cdd:PTZ00121 1652 LKKA-EEENKIKAAEEAKKAEEDKKKAEEAKKAEEDEKKAAEALKKEAEEAKKAEELKKKEAEEKKKAEELKKAEEENKI 1730

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1030 ----LDSKGEKRKRKTEEKSVDkdfESSSMKISKVEGTEIVKPSPKRKMEGDV--EKLERTPEKDKIASSTTpAKKIKLN 1103
Cdd:PTZ00121 1731 kaeeAKKEAEEDKKKAEEAKKD---EEEKKKIAHLKKEEEKKAEEIRKEKEAVieEELDEEDEKRRMEVDKK-IKDIFDN 1806

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 148685338 1104 RETGKKIGNAEN----------ASTTKEPSEKLESTSSKIKQEKVKGKAKRKVAGSEGSSSTlvDYTSTSSTGGSPVRKS 1173
Cdd:PTZ00121 1807 FANIIEGGKEGNlvindskemeDSAIKEVADSKNMQLEEADAFEKHKFNKNNENGEDGNKEA--DFNKEKDLKEDDEEEI 1884

                         410       420       430       440       450       460       470
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 148685338 1174 EEKTDTKRTVIKTME-EYNNDNTAPAEDVIImiqvpQSKWDKDDFESEEEDvKTTQPIQSVGKPSSIIKNVTTK 1246
Cdd:PTZ00121 1885 EEADEIEKIDKDDIErEIPNNNMAGKNNDII-----DDKLDKDEYIKRDAE-ETREEIIKISKKDMCINDFSSK 1952

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.

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                  ....*....|....*....|....*....|....*....|...
gi 148685338  150 CLICKDIMTDA--VVIPCCGNSYCDECIRTALLESDEHtCPTC 190
Cdd:cd00162     1 CPICREEMNDRrpVVLLSCGHTFSRSAIARWLEGSKQK-CPFC 42

RING finger, HC subclass, found in really interesting new gene 1 protein (RING1) and similar proteins; RING1, also known as polycomb complex protein RING1, RING finger protein 1 (RNF1), or RING finger protein 1A (RING1A), was identified as a transcriptional repressor that is associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. It is a core component of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase that transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119. PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing. RING1 interacts with multiple PcG proteins and displays tumorigenic activity. It also shows zinc-dependent DNA binding activity. Moreover, RING1 inhibits transactivation of the DNA-binding protein recombination signal binding protein-Jkappa (RBP-J) by Notch through interaction with the LIM domains of KyoT2. RING1 contains a C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 148685338  147 ELLCLICKDIMTDAVVIPCCGNSYCDECIRTAlLESDEHTCPTCHQNDVSPDAL 200
Cdd:cd16739     3 ELMCPICLDMLKNTMTTKECLHRFCSDCIVTA-LRSGNKECPTCRKKLVSKRSL 55

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Deltex3 (DTX3), Deltex-3-like (DTX3L) and similar proteins; This subfamily contains Deltex3 (DTX3) and Deltex-3-like (DTX3L), both of which are E3 ubiquitin-protein ligases belonging to the Deltex (DTX) family. DTX3, also known as RING finger protein 154 (RNF154), has a biological function that remains unclear. DTX3L, also known as B-lymphoma- and BAL-associated protein (BBAP) or Rhysin-2 (Rhysin2), regulates endosomal sorting of the G protein-coupled receptor CXCR4 from endosomes to lysosomes. It also regulates subcellular localization of its partner protein, B aggressive lymphoma (BAL), by a dynamic nucleocytoplasmic trafficking mechanism. In contrast to other DTXs, both DTX3 and DTX3L contain a C3HC4-type RING-HC finger, and a previously unidentified C-terminal domain. DTX3L can associate with DTX1 through its unique N termini and further enhance self-ubiquitination.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 148685338  150 CLICKDIMTDAVVIPCCGNSYCDECIRTALleSDEHTCPTC 190
Cdd:cd16506     3 CPICLDEIQNKKTLEKCKHSFCEDCIDRAL--QVKPVCPVC 41

RING finger, HC subclass, found in RING finger protein RNF5, RNF185 and similar proteins; RNF5 and RNF185 are E3 ubiquitin-protein ligases that are anchored to the outer membrane of the endoplasmic reticulum (ER). RNF5 acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis, and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. RNF185 controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical endoplasmic reticulum-associated degradation (ERAD) model substrates. Moreover, both RNF5 and RNF185 play important roles in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) are also included in this family. They possess E3 ubiquitin-protein ligase activity and may play a role in the growth and development of Arabidopsis. All members of this family contain a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 148685338  150 CLICKDIMTDAVViPCCGNSYCDECIRTALLESDEH-TCPTC 190
Cdd:cd16534     3 CNICLDTASDPVV-TMCGHLFCWPCLYQWLETRPDRqTCPVC 43

RING finger, HC subclass, found in tripartite motif-containing protein 38 (TRIM38) and similar proteins; TRIM38, also known as RING finger protein 15 (RNF15) or zinc finger protein RoRet, is an E3 ubiquitin-protein ligase that promotes K63- and K48-linked ubiquitination of cellular proteins and also catalyzes self-ubiquitination. It negatively regulates Tumor necrosis factor alpha (TNF-alpha)- and interleukin-1beta-triggered Nuclear factor-kappaB (NF-kappaB) activation by mediating lysosomal-dependent degradation of transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1)-binding protein (TAB)2/3, two critical components of the TAK1 kinase complex. It also inhibits TLR3/4-mediated activation of NF-kappaB and interferon regulatory factor 3 (IRF3) by mediating ubiquitin-proteasomal degradation of TNF receptor-associated factor 6 (Traf6) and NAK-associated protein 1 (Nap1), respectively. Moreover, TRIM38 negatively regulates TLR3-mediated interferon beta (IFN-beta) signaling by targeting ubiquitin-proteasomal degradation of TIR domain-containing adaptor inducing IFN-beta (TRIF). It functions as a valid target for autoantibodies in primary Sjogren's Syndrome. TRIM38 belongs the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 148685338  146 DELLCLICKDIMTDAVVIPcCGNSYCDECIRTAL-----LESDEHT--CPTCH 191
Cdd:cd16600     4 EEATCSICLQLMTEPVSIN-CGHSYCKRCIVSFLenqsqLEPGLETfsCPQCR 55

RING finger, HC subclass, found in bifunctional apoptosis regulator (BAR); BAR, also known as RING finger protein 47, was originally identified as an inhibitor of Bax-induced apoptosis. It participates in the block of apoptosis induced by TNF-family death receptors (extrinsic pathway) and mitochondria-dependent apoptosis (intrinsic pathway). BAR is predominantly expressed by neurons in the central nervous system and is involved in the regulation of neuronal survival. It is an endoplasmic reticulum (ER)-associated RING-type E3 ubiquitin ligase that interacts with BI-1 protein and post-translationally regulates its stability, as well as functioning in ER stress. BAR contains an N-terminal C3HC4-type RING-HC finger, a SAM domain, a coiled-coil domain, and a C-terminal transmembrane (TM) domain. This model corresponds to the RING-HC finger responsible for the binding of ubiquitin conjugating enzymes (E2s).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 148685338  147 ELLCLICKDIMTDAVVIPCcGNSYCDECIRTALLESDEHTCPTCHQ 192
Cdd:cd16497     1 EFLCHCCYDLLVNPTTLNC-GHSFCRHCLALWWKSSKKTECPECRQ 45