first RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the first RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2217394932 154 DGFKCRKCHGFLSDPVSLSCGHTFCKLCLERGRAadRRCALCGVKLSAL 202
Cdd:cd16513     1 DLLSCPLCRGLLFEPVTLPCGHTFCKRCLERDPS--SRCRLCRLKLSPG 47

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 497 TDQGDKPALSLP-LASFDASDLeCALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCKD-----------GLSQCL 564
Cdd:COG5432     6 TDPSDWNQTKIPsLKGLDSMLR-CRICDCRISIPCETTCGHTFCSLCIRRHLGTQPFCPVCREdpcesrlrgssGSREIN 84

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2217394932 565 ASRKYSKNVIMEEL-IAKFLPEELKERRKLYEEEMEE 600
Cdd:COG5432    85 ESHARNRDLLRKVLeSLCRLPRPIKEERPCRWETVIA 121

first RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the first RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2217394932 154 DGFKCRKCHGFLSDPVSLSCGHTFCKLCLERGRAadRRCALCGVKLSAL 202
Cdd:cd16513     1 DLLSCPLCRGLLFEPVTLPCGHTFCKRCLERDPS--SRCRLCRLKLSPG 47

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 497 TDQGDKPALSLP-LASFDASdLECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCKDGLSQClasrKYSKNVIM 575
Cdd:TIGR00599   7 TDSSDWLTTPIPsLYPLDTS-LRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLCRAEDQES----KLRSNWLV 81

                  ....*..
gi 2217394932 576 EELIAKF 582
Cdd:TIGR00599  82 SEIVESF 88

mitochondrial precursor proteins import receptor (72 kDa mitochondrial outermembrane protein) (mitochondrial import receptor for the ADP/ATP carrier) (translocase of outermembrane tom70); [Transport and binding proteins, Amino acids, peptides and amines]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 243 ASQLRHEGNRLYRERQVEAALLKYNEAVKLAPnDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAHFRKAQALA 322
Cdd:TIGR00990 127 AAKLKEKGNKAYRNKDFNKAIKLYSKAIECKP-DPVYYSNRAACHNALGDWEKVVEDTTAALELDPDYSKALNRRANAYD 205

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 323 TLGKVEEALREFLYCVSLDGKNKRARCEAQRLLLSFFSPS----VPGDSQEHSPDI------LKLLAPHPR---LKENVE 389
Cdd:TIGR00990 206 GLGKYADALLDLTASCIIDGFRNEQSAQAVERLLKKFAESkakeILETKPENLPSVtfvgnyLQSFRPKPRpagLEDSNE 285

                         170       180       190
                  ....*....|....*....|....*....|..
gi 2217394932 390 SmtTEVTSHNLPRLLQDNLELPHCSSQEEAAA 421
Cdd:TIGR00990 286 L--DEETGNGQLQLGLKSPESKADESYEEAAR 315

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 497 TDQGDKPALSLP-LASFDASDLeCALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCKD-----------GLSQCL 564
Cdd:COG5432     6 TDPSDWNQTKIPsLKGLDSMLR-CRICDCRISIPCETTCGHTFCSLCIRRHLGTQPFCPVCREdpcesrlrgssGSREIN 84

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2217394932 565 ASRKYSKNVIMEEL-IAKFLPEELKERRKLYEEEMEE 600
Cdd:COG5432    85 ESHARNRDLLRKVLeSLCRLPRPIKEERPCRWETVIA 121

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCL--ERCLDHNAKCPLCK 557
Cdd:COG5574   215 DYKCFLCLEEPEVPSCTPCGHLFCLSCLliSWTKKKYEFCPLCR 258

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2217394932 156 FKCRKCHGFLSDPVSLSCGHTFCKLCLERGRAADRRCALC 195
Cdd:TIGR00599  27 LRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLC 66

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 2217394932 157 KCRKCHGFLSDPVSLSCGHTFCKLCLERGRAADRRCALC 195
Cdd:COG5432    27 RCRICDCRISIPCETTCGHTFCSLCIRRHLGTQPFCPVC 65

ATP-dependent protease La (LON) substrate-binding domain; This domain has been shown to be part of the PUA superfamily. This domain represents a general protein and polypeptide interaction domain for the ATP-dependent serine peptidase, LON, Peptidase_S16, pfam05362. ATP-dependent Lon proteases are conserved in all living organizms and catalyze rapid turnover of short-lived regulatory proteins and many damaged or denatured proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2217394932 607 NVPIFVC--TMAYPTVPCPLHIFEPCYRLMIRRCIETGtRQFGMCL 650
Cdd:pfam02190   1 ELPLLPLrnTVLFPGMVLPLFVGRPRSIAAIEAALNKD-KLYGVLL 45

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 2217394932  158 CRKCHG-FLSDPVSLSCGHTFCKLCLER-GRAADRRCALC 195
Cdd:smart00184   1 CPICLEeYLKDPVILPCGHTFCRSCIRKwLESGNNTCPIC 40

first RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the first RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2217394932 154 DGFKCRKCHGFLSDPVSLSCGHTFCKLCLERGRAadRRCALCGVKLSAL 202
Cdd:cd16513     1 DLLSCPLCRGLLFEPVTLPCGHTFCKRCLERDPS--SRCRLCRLKLSPG 47

RING finger, HC subclass, found in constitutive photomorphogenesis protein 1 (COP1) and similar proteins; COP1, also known as RING finger and WD repeat domain protein 2 (RFWD2) or RING finger protein 200 (RNF200), is a central regulator of photomorphogenic development in plants, which targets key transcription factors for proteasome-dependent degradation. It is localized predominantly in the nucleus, but may also be present in the cytosol. Mammalian COP1 functions as an E3 ubiquitin-protein ligase that interacts with Jun transcription factors and modulates their transcriptional activity. It also interacts with and negatively regulates the tumor-suppressor protein p53. Moreover, COP1 associates with COP9 signalosome subunit 6 (CSN6), and is involved in 14-3-3sigma ubiquitin-mediated degradation. The CSN6-COP1 link enhances ubiquitin-mediated degradation of p27(Kip1), a critical CDK inhibitor involved in cell cycle regulation, to promote cancer cell growth. Furthermore, COP1 functions as the negative regulator of ETV1 and influences prognosis in triple-negative breast cancer. COP1 contains an N-terminal extension, a C3HC4-type RING-HC finger, a coiled coil domain, and seven WD40 repeats. In human COP1, a classic leucine-rich NES, and a novel bipartite NLS is bridged by the RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2217394932 515 SDLECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCKDGLS 561
Cdd:cd16504     1 NDFLCPICFDIIKEAFVTKCGHSFCYKCIVKHLEQKNRCPKCNFYLT 47

Tetratricopeptide (TPR) repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 235 KLFPGPARAsqLRHEGNRLYRERQVEAALLKYNEAVKLAPNDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAH 314
Cdd:COG0457    36 ELDPDDAEA--LYNLGLAYLRLGRYEEALADYEQALELDPDDAEALNNLGLALQALGRYEEALEDYDKALELDPDDAEAL 113

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 2217394932 315 FRKAQALATLGKVEEALREFLYCVSLDGKNKRARCEAQRLLLS 357
Cdd:COG0457   114 YNLGLALLELGRYDEAIEAYERALELDPDDADALYNLGIALEK 156

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 2217394932 517 LECALCMRLFYEPVTTPCGHTFCLKCLERCLDH-NAKCPLC 556
Cdd:cd16449     1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESgSIKCPIC 41

Outer membrane protein chaperone/metalloprotease BepA/YfgC, contains M48 and TPR domains [Cell wall/membrane/envelope biogenesis, Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 241 ARASQLRHEGNRLYRERQVEAALLKYNEAVKLAPNDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAHFRKAQA 320
Cdd:COG4783     2 ACAEALYALAQALLLAGDYDEAEALLEKALELDPDNPEAFALLGEILLQLGDLDEAIVLLHEALELDPDEPEARLNLGLA 81

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2217394932 321 LATLGKVEEALREFLYCVSLDGKNKRARCEAQRLLL 356
Cdd:COG4783    82 LLKAGDYDEALALLEKALKLDPEHPEAYLRLARAYR 117

Tetratricopeptide (TPR) repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 240 PARASQLRHEGNRLYRERQVEAALLKYNEAVKLAPNDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAHFRKAQ 319
Cdd:COG0457     5 PDDAEAYNNLGLAYRRLGRYEEAIEDYEKALELDPDDAEALYNLGLAYLRLGRYEEALADYEQALELDPDDAEALNNLGL 84

                          90       100
                  ....*....|....*....|....*....
gi 2217394932 320 ALATLGKVEEALREFLYCVSLDGKNKRAR 348
Cdd:COG0457    85 ALQALGRYEEALEDYDKALELDPDDAEAL 113

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 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLER----CLDHNAKCPLCK 557
Cdd:cd16597     5 ELTCSICLELFKDPVTLPCGHNFCGVCIEKtwdsQHGSEYSCPQCR 50

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2217394932 518 ECALCMRLFYEP-VTTPCGHTFCLKCLERCLDHNAKCPLC 556
Cdd:pfam13923   1 MCPICMDMLKDPsTTTPCGHVFCQDCILRALEASNECPLC 40

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
                  ....*....|....*....|....*....|....*....|....*..
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLE----RCLDHNAKCPLCKD 558
Cdd:cd16609     3 ELTCSICLGLYQDPVTLPCQHSFCRACIEdhwrQKDEGSFSCPECRA 49

RING finger, HC subclass, found in Arabidopsis thaliana proteolysis 1 protein (PRT1) and similar proteins; PRT1, also called RING-type E3 ubiquitin transferase PRT1, is an E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. It functions in the N-end rule pathway of protein degradation, where it specifically recognizes and ubiquitinates proteins with an N-terminal bulky aromatic amino acid (Phe). It does not act on aliphatic hydrophobic and basic N-terminal residues (Arg or Leu) containing proteins. PRT1 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLERCLD--HNAKCPLCKD 558
Cdd:cd23132     2 EFLCCICLDLLYKPVVLECGHVFCFWCVHRCMNgyDESHCPLCRR 46

RING finger, HC subclass, found in breast cancer type 1 susceptibility protein (BRCA1) and similar proteins; BRCA1, also known as RING finger protein 53 (RNF53), is a RING finger protein encoded by the tumor suppressor gene BRCA1 that regulates all DNA double-strand break (DSB) repair pathways. BRCA1 is frequently mutated in patients with hereditary breast and ovarian cancer (HBOC). Its mutation is also associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. It plays an important role in the DNA damage response signaling and has been implicated in various cellular processes such as cell cycle regulation, transcriptional regulation, chromatin remodeling, DNA DSBs, and apoptosis. BRCA1 contains an N-terminal C3HC4-type RING-HC finger, and two BRCT (BRCA1 C-terminus domain) repeats at the C-terminus.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 517 LECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAK---CPLCKDGLSQclasRKYSKNVIMEELIAKFL 583
Cdd:cd16498    17 LECPICLELLKEPVSTKCDHQFCRFCILKLLQKKKKpapCPLCKKSVTK----RSLQESTRFKQLVEAVK 82

Outer membrane protein chaperone/metalloprotease BepA/YfgC, contains M48 and TPR domains [Cell wall/membrane/envelope biogenesis, Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 235 KLFPGPARASQLRheGNRLYRERQVEAALLKYNEAVKLAPNDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAH 314
Cdd:COG4783    32 ELDPDNPEAFALL--GEILLQLGDLDEAIVLLHEALELDPDEPEARLNLGLALLKAGDYDEALALLEKALKLDPEHPEAY 109

                          90       100       110
                  ....*....|....*....|....*....|
gi 2217394932 315 FRKAQALATLGKVEEALREFLYCVSLDGKN 344
Cdd:COG4783   110 LRLARAYRALGRPDEAIAALEKALELDPDD 139

RING finger, HC subclass, found in Saccharomyces cerevisiae radiation sensitivity protein 18 (RAD18) and similar proteins; RAD18, also called RING-type E3 ubiquitin transferase RAD18, acts as a postreplication repair E3 ubiquitin-protein ligase that associates with the E2 ubiquitin conjugating enzyme UBC2/RAD6 to form the UBC2-RAD18 ubiquitin ligase complex involved in postreplicative repair (PRR) of damaged DNA. The UBC2-RAD18 complex cooperates with RAD5 and the UBC13-MMS2 dimer to attach mono-ubiquitin chains on 'Lys-164' of POL30, which is necessary for PRR. The UBC2-RAD18 complex is also involved in prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine. RAD18 is an E3 RING-finger protein belonging to the UBC2/RAD6 epistasis group. It contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 2217394932 517 LECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCK 557
Cdd:cd23148     4 LRCHICKDLLKAPMRTPCNHTFCSFCIRTHLNNDARCPLCK 44

RING finger, HC subclass, found in tripartite motif-containing protein 47 (TRIM47) and similar proteins; TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), 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, 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. It plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. This subfamily also includes RING finger protein 135 (RNF135). RNF135, also known as RIG-I E3 ubiquitin ligase (REUL) or Riplet, is a widely expressed E3 ubiquitin-protein ligase that consists of an N-terminal C3HC4-type RING-HC finger and C-terminal B30.2/SPRY and PRY motifs, but lacks the B-box and coiled-coil domains that are also typically present in TRIM proteins. RNF135 serves as a specific retinoic acid-inducible gene-I (RIG-I)-interacting protein that ubiquitinates RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity to produce antiviral type-I interferon (IFN) during the early phase of viral infection. It also has been identified as a bio-marker and therapy target of glioblastoma. It associates with the ERK signal transduction pathway and plays a role in glioblastoma cell proliferation, migration and cell cycle.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2217394932 517 LECALCMRLFYEPVTTPCGHTFCLKCLERCLDHN----AKCPLCKDGLS 561
Cdd:cd16604     1 LSCPICLDLLKDPVTLPCGHSFCMGCLGALWGAGrggrASCPLCRQTFP 49

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2217394932 518 ECALCMRLFYEP---VTTPCGHTFCLKCLERCLDHNAKCPLCK 557
Cdd:pfam13639   2 ECPICLEEFEEGdkvVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

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 2217394932 515 SDLECALCMRLFYEPVTTPCGHTFCLKCLERCLD-HNAKCPLCKDGLSQ 562
Cdd:cd16509     2 SDEECAICLDSLTNPVITPCAHVFCRRCICEVIQrEKAKCPMCRAPLSA 50

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 2217394932  519 CALCM-RLFYEPVTTPCGHTFCLKCLERCLD-HNAKCPLC 556
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLEsGNNTCPIC 40

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
                  ....*....|....*....|....*....|....*....|....*...
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAK--CPLCKDGLS 561
Cdd:cd16599     4 ELLCPICYEPFREAVTLRCGHNFCKGCVSRSWERQPRapCPVCKEASS 51

RING finger, HC subclass, found in RING finger protein 213 (RNF213) and similar proteins; RNF213, also known as ALK lymphoma oligomerization partner on chromosome 17 or Moyamoya steno-occlusive disease-associated AAA+ and RING finger protein (mysterin), is an intracellular soluble protein that functions as an E3 ubiquitin-protein ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. It plays a unique role in endothelial cells for proper gene expression in response to inflammatory signals from the environment. Mutations in RNF213 may be associated with Moyamoya disease (MMD), an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. It also acts as a nuclear marker for acanthomorph phylogeny. RNF213 contains two tandem enzymatically active AAA+ ATPase modules and a C3HC4-type RING-HC finger. It can form a huge ring-shaped oligomeric complex.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2217394932 518 ECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPLCK 557
Cdd:cd16561     4 ECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMSCPLCR 43

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2217394932 519 CALCMRLFYEPV-TTPCGHTFCLKCLERCLDHNA-KCPLC 556
Cdd:pfam00097   1 CPICLEEPKDPVtLLPCGHLFCSKCIRSWLESGNvTCPLC 40

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 2217394932 518 ECALCMRLFYEPVTTPCGHTFCLKCLERCLD---HNAKCPLCK 557
Cdd:cd16534     2 ECNICLDTASDPVVTMCGHLFCWPCLYQWLEtrpDRQTCPVCK 44

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM13, TRIM59 and similar proteins; TRIM13 and TRIM59, two closely related tripartite motif-containing proteins, belong to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, followed by a C-terminal transmembrane domain. TRIM13, also known as B-cell chronic lymphocytic leukemia tumor suppressor Leu5, leukemia-associated protein 5, putative tumor suppressor RFP2, RING finger protein 77 (RNF77), or Ret finger protein 2, is an endoplasmic reticulum (ER) membrane anchored E3 ubiquitin-protein ligase that interacts with proteins localized to the ER, including valosin-containing protein (VCP), a protein indispensable for ER-associated degradation (ERAD). TRIM59, also known as RING finger protein 104 (RNF104) or tumor suppressor TSBF-1, is a putative E3 ubiquitin-protein ligase that functions as a novel multiple cancer biomarker for immunohistochemical detection of early tumorigenesis.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2217394932 515 SDLECALCMRLFYEPVTTPCGHTFCLKCLE-------RCLDHNAKCPLCK 557
Cdd:cd16581     1 EELTCSICYNIFDDPKILPCSHTFCKNCLEkllaasgYYLLASLKCPTCR 50

RING finger, HC subclass, found in ligand of numb protein X 3 (LNX3); LNX3, also known as PDZ domain-containing RING finger protein 3 (PDZRN3), or Semaphorin cytoplasmic domain-associated protein 3 (SEMACAP3), is an E3 ubiquitin-protein ligase that was first identified as a Semaphorin-binding partner. It is also responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX3 acts as a negative regulator of osteoblast differentiation by inhibiting Wnt-beta-catenin signaling. LNX3 also plays an important role in neuromuscular junction formation. It interacts with and ubiquitinates the muscle specific tyrosine kinase (MuSK), thus promoting its endocytosis and negatively regulating the cell surface expression of this key regulator of postsynaptic assembly. LNX3 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPL 555
Cdd:cd16718     4 DFKCNLCNKVLEDPLTTPCGHVFCAGCVLPWVVQQGSCPV 43

second RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the second RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2217394932 156 FKCRKCHGFLSDPVSLSCGHTFCKLCLERGRAADRRCALCGVKL 199
Cdd:cd16514     2 LECSLCLRLLYEPVTTPCGHTFCRACLERCLDHSPKCPLCRTSL 45

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2217394932 516 DLECALCMRLFYEPVTT-PCGHTFCLKCLERCLDH-NAKCPLCKD 558
Cdd:cd16544     2 ELTCPVCQEVLKDPVELpPCRHIFCKACILLALRSsGARCPLCRG 46

Lipopolysaccharide biosynthesis regulator YciM/LapB, contains six TPR domains and a C-terminal metal-binding domain [Cell wall/membrane/envelope biogenesis];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217394932 252 RLYRER-QVEAALLKYNEAVKLAPNDHLLYSNRSQIYFTLESHENALHDAEIACKLRPMGFKAHFRKAQALATLGKVEEA 330
Cdd:COG2956    50 NLYRRRgEYDRAIRIHQKLLERDPDRAEALLELAQDYLKAGLLDRAEELLEKLLELDPDDAEALRLLAEIYEQEGDWEKA 129

                          90       100
                  ....*....|....*....|....*.
gi 2217394932 331 LREFLYCVSLDGKNKRARCEAQRLLL 356
Cdd:COG2956   130 IEVLERLLKLGPENAHAYCELAELYL 155

RING finger, HC subclass, found in ligand of numb protein X 4 (LNX4); LNX4, also known as PDZ domain-containing RING finger protein 4 (PDZRN4), or SEMACAP3-like protein (SEMCAP3L), is an E3 ubiquitin-protein ligase responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX4 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2217394932 514 ASDLECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAKCPL 555
Cdd:cd16719     2 DPDLKCKLCGKVLEEPLSTPCGHVFCAGCLLPWAVQRRLCPL 43

RING finger, HC subclass, found in ubiquitin-like PHD and RING finger domain-containing proteins, UHRF1 and UHRF2, and similar proteins; UHRF1 is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumor suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of transcription factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF2 was originally identified as a ubiquitin ligase acting as a small ubiquitin-like modifier (SUMO) E3 ligase that enhances zinc finger protein 131 (ZNF131) SUMOylation, but does not enhance ZNF131 ubiquitination. It also ubiquitinates PCNP, a PEST-containing nuclear protein. Moreover, UHRF2 functions as a nuclear protein involved in cell-cycle regulation and has been implicated in tumorigenesis. It interacts with cyclins, CDKs, p53, pRB, PCNA, HDAC1, DNMTs, G9a, methylated histone H3 lysine 9, and methylated DNA. It interacts with the cyclin E-CDK2 complex, ubiquitinates cyclins D1 and E1, induces G1 arrest, and is involved in the G1/S transition regulation. Furthermore, UHRF2 is a direct transcriptional target of the transcription factor E2F-1 in the induction of apoptosis. It recruits HDAC1 and binds to methyl-CpG. UHRF2 also participates in the maturation of Hepatitis B virus (HBV) by interacting with the HBV core protein and promoting its degradation. Both UHRF1 and UHRF2 contain an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) finger, a SET- and RING-associated (SRA) domain, and a C-terminal C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2217394932 518 ECALCMRLFYEPVTTPCGHTFCLKCLERCLDHNAK-CPLCKDGL 560
Cdd:cd16613     2 TCICCQELVYKPITTPCKHNICKSCLQRSFKAEVYtCPACRHDL 45

RING finger, HC subclass, found in RING finger protein 125 (RNF125); RNF125, also known as T-cell RING activation protein 1 (TRAC-1), is an E3 ubiquitin-protein ligase that is predominantly expressed in lymphoid cells, and functions as a positive regulator of T cell activation. It also down-modulates HIV replication and inhibits pathogen-induced cytokine production. It negatively regulates type I interferon signaling, which conjugates Lys(48)-linked ubiquitination to retinoic acid-inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. Further, RNF125 conjugates ubiquitin to melanoma differentiation-associated gene 5 (MDA5), a family protein of RIG-I. It thus acts as a negative regulator of RIG-I signaling, and is a direct target of miR-15b in the context of Japanese encephalitis virus (JEV) infection. Moreover, RNF125 binds to and ubiquitinates JAK1, prompting its degradation and inhibition of receptor tyrosine kinase (RTK) expression. It also negatively regulates p53 function through physical interaction and ubiquitin-mediated proteasome degradation. Mutations in RNF125 may lead to overgrowth syndromes (OGS). RNF125, together with three closely related proteins: RNF114, RNF138 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM). The UIM of RNF125 binds K48-linked poly-ubiquitin chains and is, together with the RING domain, required for auto-ubiquitination.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2217394932 516 DLECALCMRLFYEPVTTPCGHTFCLKCLERCL-DHNAKCPLCKDGLS 561
Cdd:cd16542     1 NFDCAVCLEVLHQPVRTRCGHVFCRPCIATSLrNNTWTCPYCRAYLS 47

RING finger, HC subclass, found in tripartite motif-containing protein 13 (TRIM13) and similar proteins; TRIM13, also known as B-cell chronic lymphocytic leukemia tumor suppressor Leu5, leukemia-associated protein 5, putative tumor suppressor RFP2, RING finger protein 77 (RNF77), or Ret finger protein 2, is an endoplasmic reticulum (ER) membrane anchored E3 ubiquitin-protein ligase that interacts with proteins localized to the ER, including valosin-containing protein (VCP), a protein indispensable for ER-associated degradation (ERAD). It also targets the known ER proteolytic substrate CD3-delta, but not the N-end rule substrate Ub-R-YFP (yellow fluorescent protein) for degradation. Moreover, TRIM13 regulates ubiquitination and degradation of NEMO to suppress tumor necrosis factor (TNF) induced nuclear factor-kappaB (NF- kappa B) activation. It is also involved in NF-kappaB p65 activation and nuclear factor of activated T-cells (NFAT)-dependent activation of c-Rel upon T-cell receptor engagement. Furthermore, TRIM13 negatively regulates melanoma differentiation-associated gene 5 (MDA5)-mediated type I interferon production. It also regulates caspase-8 ubiquitination, translocation to autophagosomes, and activation during ER stress induced cell death. Meanwhile, TRIM13 enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation. TRIM13 belongs to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region. In addition, TRIM13 contains a C-terminal transmembrane domain.