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
                 ....*....|....*....|....*....|....*....
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRG-NCPLC 223
Cdd:cd16449    3 CPICLERLKDPVLLPCGHVFCRECIRRLLESGSiKCPIC 41

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
                  ....*....|....*....|....*....|....*...
gi 357513375  186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:TIGR00599  29 CHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLC 66

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
                 ....*....|....*....|....*....|....*....
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRG-NCPLC 223
Cdd:cd16449    3 CPICLERLKDPVLLPCGHVFCRECIRRLLESGSiKCPIC 41

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 5 (XBAT35) and similar proteins; XBAT35, also known as ankyrin repeat domain and RING finger-containing protein XBAT35, or RING-type E3 ubiquitin transferase XBAT35, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. It contains a typical C3HC4-type RING-HC finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 357513375 186 CCVCMVRDKGAAFIPCGH-TFCRMCSRELWVSRGNCPLCNHFILEVLDIF 234
Cdd:cd23129    5 CVVCMDAPRDAVCVPCGHvAGCMSCLKALMQSSPLCPICRAPVRQVIKVY 54

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 357513375   186 CCVCM-VRDKGAAFIPCGHTFCRMCSRELWVSRGN-CPLC 223
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLESGNNtCPIC 40

Modified RING finger, HC subclass (C2H2C4-type), found in E3 ubiquitin-protein ligase MDM2, protein MDM4 and similar proteins; MDM2 (also known as HDM2) and MDM4 (also known as MDMX or HDMX) are the primary p53 tumor suppressor negative regulators. They have non-redundant roles in the regulation of p53. MDM2 mainly functions to control p53 stability, while MDM4 controls p53 transcriptional activity. Both MDM2 and MDM4 contain an N-terminal p53-binding domain, a RanBP2-type zinc finger (zf-RanBP2) domain near the central acidic region, and a C-terminal modified C2H2C4-type RING-HC finger. Mdm2 can form homo-oligomers through its RING domain and displays E3 ubiquitin ligase activity that catalyzes the attachment of ubiquitin to p53 as an essential step in the regulation of its levels in cells. Despite its RING domain and structural similarity with MDM2, MDM4 does not homo-oligomerize and lacks ubiquitin-ligase function, but inhibits the transcriptional activity of p53. In addition, both their RING domains are responsible for the hetero-oligomerization, which is crucial for the suppression of P53 activity during embryonic development and the recruitment of E2 ubiquitin-conjugating enzymes. Moreover, MDM2 and MDM4 can be phosphorylated and destabilized in response to DNA damage stress. In response to ribosomal stress, MDM2-mediated p53 ubiquitination and degradation can be inhibited through the interaction with ribosomal proteins L5, L11, and L23. However, MDM4 is not bound to ribosomal proteins, suggesting its different response to regulation by small basic proteins such as ribosomal proteins and ARF.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 357513375 186 CCVCMVRDKGAAFI--PCGHTF-CRMCSRELWVSRGNCPLCNHFILEVL 231
Cdd:cd16646    3 CVICLSRPRTAAIVhgKTGHQVaCYTCAKKLKRRGKPCPVCRRPIQNVI 51

RING finger, HC subclass, found in RING finger protein 141 (RNF141) and similar proteins; RNF141, also known as zinc finger protein 230 (ZNF230), is a RING finger protein present primarily in the nuclei of spermatogonia, the acrosome, and the tail of spermatozoa. It may have a broad function during early development of vertebrates. It plays an important role in spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization. It also exhibits DNA binding activity. RNF141/ZNF230 gene mutations may be associated with azoospermia. RNF141 contains a C3HC4-type RING finger domain that may function as an activator module in transcription.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 357513375 186 CCVCMVRdKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:cd16545    3 CCICMDR-KADLILPCAHSYCQKCIDKWSDRHRTCPIC 39

RING finger, HC subclass, found in inhibitor of apoptosis proteins (IAPs); IAPs are frequently overexpressed in cancer and associated with tumor cell survival, chemoresistance, disease progression, and poor prognosis. They function primarily as negative regulators of cell death. They regulate caspases and apoptosis through the inhibition of specific members of the caspase family of cysteine proteases. In addition, IAPs has been implicated in a multitude of other cellular processes, including inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis. IAPs in this family includes cellular inhibitor of apoptosis protein c-IAP1 (BIRC2) and c-IAP2 (BIRC3), XIAP (BIRC4), BIRC7, and BIRC8, all of which contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. The UBA domain is only absent in mammalian homologs of BIRC7. Moreover, c-IAPs contains an additional caspase activation and recruitment domain (CARD) between the UBA and C3HC4-type RING-HC domains. The CARD domain may serve as a protein interaction surface.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 357513375 183 EHNCCVCMVRDKGAAFIPCGHTF-CRMCSRELwvsrGNCPLC 223
Cdd:cd16510    1 EKLCKICMDREVNIVFLPCGHLVtCAQCAASL----RKCPIC 38

RING finger, HC subclass, found in E3 ubiquitin-protein ligase XIAP, baculoviral IAP repeat-containing protein 8 (BIRC8) and similar proteins; XIAP, also known as baculoviral IAP repeat-containing protein 4 (BIRC4), IAP-like protein (ILP), inhibitor of apoptosis protein 3 (IAP-3), or X-linked inhibitor of apoptosis protein (X-linked IAP), is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases, including caspase-3, -7, and -9. It promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. The ubiquitin-protein ligase (E3) activity of XIAP also exhibits in the ubiquitination of second mitochondria-derived activator of caspases (Smac). The mitochondrial proteins, Smac/DIABLO and Omi/HtrA2, can inhibit the antiapoptotic activity of XIAP. XIAP has also been implicated in several intracellular signaling cascades involved in the cellular response to stress, such as the c-Jun N-terminal kinase (JNK), the nuclear factor-kappaB (NF-kappaB), and the transforming growth factor-beta (TGF-beta) pathways. Moreover, XIAP can regulate copper homeostasis by interacting with MURR1. BIRC8, also known as inhibitor of apoptosis-like protein 2, IAP-like protein 2, ILP-2, or testis-specific inhibitor of apoptosis, is a tissue-specific homolog of E3 ubiquitin-protein ligase XIAP. It has been implicated in the control of apoptosis in the testis by direct inhibition of caspase 9. Both XIAP and BIRC8 contain three N-terminal baculoviral IAP repeat (BIR) domains, a ubiquitin-association (UBA) domain and a C3HC4-type RING-HC finger at the carboxyl terminus.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 357513375 183 EHNCCVCMVRDKGAAFIPCGHTF-CRMCSRELwvsrGNCPLCNHFILEVLDIF 234
Cdd:cd16714   14 EKLCKICMDRNISIVFIPCGHLVtCKQCAEAL----DKCPICCTVITFKQKIF 62

RING finger, HC subclass, found in yeast Bre1 and its homologs from eukaryotes; Bre1 is an E3 ubiquitin-protein ligase that catalyzes monoubiquitination of histone H2B in concert with the E2 ubiquitin-conjugating enzyme, Rad6. The Rad6-Bre1-mediated histone H2B ubiquitylation modulates the formation of double-strand breaks (DSBs) during meiosis in yeast. it is also required, indirectly, for the methylation of histone 3 on lysine 4 (H3K4) and 79. RNF20, also known as BRE1A and RNF40, also known as BRE1B, are the mammalian homologs of Bre1. They work together to form a heterodimeric Bre1 complex that facilitate the K120 monoubiquitination of histone H2B (H2Bub1), a DNA damage-induced histone modification that is crucial for recruitment of the chromatin remodeler SNF2h to DNA double-strand break (DSB) damage sites. Moreover, the Bre1 complex acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. Deficiency in the mammalian histone H2B ubiquitin ligase Bre1 leads to replication stress and chromosomal instability. All subfamily members contain a C3HC4-type RING-HC finger at its C-terminus.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 357513375 185 NCCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRG-NCPLCN 224
Cdd:cd16499    8 KCSVCNDRFKDVIITKCGHVFCNECVQKRLETRQrKCPGCG 48

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:cd16527    3 CSLCLEERRHPTATPCGHLFCWSCITEWCNEKPECPLC 40

Zinc finger, C3HC4 type (RING finger);

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 357513375  186 CCVCMVRDKGAAFI-PCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:pfam13923   2 CPICMDMLKDPSTTtPCGHVFCQDCILRALRAGNECPLC 40

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 357513375  185 NCCVC---MVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLCN 224
Cdd:pfam13639   2 ECPICleeFEEGDKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

RING finger, HC subclass, found in Equid alphaherpesvirus 1 (Equine herpesvirus 1/EHV-1) regulatory protein and similar proteins; EHV-1 regulatory protein belongs to the Vmw110 (IPC0) protein family. It contains a typical C3HC4-type RING-HC finger and binds zinc stably.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 357513375 185 NCCVCMVRDKGAAFI-PCGHTFCRMC-SRelWV-SRGNCPLCNHFILEVL 231
Cdd:cd23130    2 VCPICLDDPEDEAITlPCLHQFCYTCiLR--WLqTSPTCPLCKTPVTSII 49

Modified RING finger, HC subclass (C3HC5-type), found in mitochondrial-anchored protein ligase (MAPL) and similar proteins; MAPL, also known as MULAN, mitochondrial ubiquitin ligase activator of NFKB 1, E3 SUMO-protein ligase MUL1, E3 ubiquitin-protein ligase MUL1, growth inhibition and death E3 ligase (GIDE), putative NF-kappa-B-activating protein 266, or RING finger protein 218 (RNF218), is a multifunctional mitochondrial outer membrane protein involved in several processes specific to metazoan (multicellular animal) cells, such as NF-kappaB activation, innate immunity and antiviral signaling, suppression of PINK1/parkin defects, mitophagy in skeletal muscle, and caspase-dependent apoptosis. MAPL contains a unique BAM (beside a membrane)/GIDE (growth inhibition death E3 ligase) domain and a C-terminal modified cytosolic C3HC5-type RING-HC finger which is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 357513375 186 CCVCMVRDKGAAFIPCGHT-FCRMCSRELwVSRGNCPLCNHFILEVLDIF 234
Cdd:cd16648    4 CVICLSNPRSCVFLECGHVcSCIECYEAL-PSPKKCPICRSFIKRVVPLY 52

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
                  ....*....|....*....|....*....|....*...
gi 357513375  186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:TIGR00599  29 CHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPKCPLC 66

RING finger, HC subclass, found in neuralized-like protein 3 (NEURL3) and similar proteins; NEURL3, also known as lung-inducible neuralized-related C3HC4 RING domain protein (LINCR), is a novel inflammation-induced E3 ubiquitin-protein ligase encoded by LINCR, a glucocorticoid-attenuated response gene induced in the lung during endotoxemia. It is expressed in alveolar epithelial type II cells, preferentially interacts with the ubiquitin-conjugating enzyme UbcH6, and generates polyubiquitin chains linked via non-canonical lysine residues. Overexpression of NEURL3 in the developing lung epithelium inhibits distal differentiation and induces cystic changes in the Notch signaling pathway. NEURL3 contains an N-terminal neuralized homology repeat (NHR) domain similar to the SPRY (SPla and the RYanodine receptor) domain and a C-terminal C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 357513375 186 CCVCMVRDKGAAFIPCGHT-FCRMCSRELWVSRGNCPLCNHFILEV 230
Cdd:cd16552    4 CAICFHHTANTRLVPCGHShFCGSCAWHIFRDTARCPVCRWQIEEV 49

RING finger, HC subclass, found in Arabidopsis thaliana protein BREAST CANCER SUSCEPTIBILITY 1 homolog (AtBRCA1) and similar proteins; AtBRCA1 plays a role in DNA repair and in cell-cycle control. It is required for the repair of DNA double-strand breaks (DSBs), both natural and induced by genotoxic stress, by homologous recombination (HR). AtBRCA1 contains a typical C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 357513375 183 EHNCCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:cd23147    4 ELKCPICLSLFKSAANLSCNHCFCAGCIGESLKLSAICPVC 44

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

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:COG5432   28 CRICDCRISIPCETTCGHTFCSLCIRRHLGTQPFCPVC 65

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 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 357513375 183 EHNCCVC--MVRDKGAafIPCGHTFCRMCSRELWVSRGN---CPLC 223
Cdd:cd16601    1 EASCSLCkeYLKDPVI--IECGHNFCRACITRFWEELDGdfpCPQC 44

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
                 ....*....|....*....|....*....
gi 357513375 200 PCGHTFCRMCSRELWVSRG-NCPLCNHFI 227
Cdd:cd16544   20 PCRHIFCKACILLALRSSGaRCPLCRGPV 48

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 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLCNHFI 227
Cdd:cd16504    5 CPICFDIIKEAFVTKCGHSFCYKCIVKHLEQKNRCPKCNFYL 46

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 357513375 180 VKVEHNCCVCMVRDKGAAFIPCGHTFCRMCSRELW--VSRGNCPLC 223
Cdd:cd16599    1 FKEELLCPICYEPFREAVTLRCGHNFCKGCVSRSWerQPRAPCPVC 46

RING finger, HC subclass, found in RING finger protein 123 (RNF123) and similar proteins; RNF123, also known as Kip1 ubiquitination-promoting complex protein 1 (KPC1), is an E3 ubiquitin-protein ligase that mediates ubiquitination and proteasomal processing of the nuclear factor-kappaB 1 (NF-kappaB1) precursor p105 to the p50 active subunit that restricts tumor growth. It also regulates degradation of heterochromatin protein 1alpha (HP1alpha) and 1beta (HP1beta) in lamin A/C knock-down cells. Moreover, RNF123, together with Kip1 ubiquitylation-promoting complex 2 (KPC2), forms the Kip1 ubiquitination-promoting complex (KPC), acting as a cytoplasmic ubiquitin ligase that regulates degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) at the G1 phase of the cell cycle. RNF123 may also function as a clinically relevant, peripheral state marker of depression. RNF123 contains a C3HC4-type RING-HC finger at the C-terminus.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLCN 224
Cdd:cd16541    3 CPICYAHPIDAVFLPCGHKSCRSCINRHLMNNKECFFCK 41

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
                 ....*....|....*....|....*....|....*....
gi 357513375 186 CCVCMVRDKGAAFIPCGHTFCRMCSRE-LWVSRGNCPLC 223
Cdd:cd16509    6 CAICLDSLTNPVITPCAHVFCRRCICEvIQREKAKCPMC 44

RING finger, HC subclass, found in RNA-binding proteins of the evolutionarily-conserved MEX-3 family; MEX-3 phosphoproteins are found in vertebrates. They are mediators of post-transcriptional regulation in different organisms, and have been implicated in many core biological processes, including embryonic development, epithelial homeostasis, immune responses, metabolism, and cancer. They contain two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. They shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. The RNA-binding protein MEX-3 from nematode Caenorhabditis elegans is the founding member of the MEX-3 family. Due to the lack of a RING-HC finger, it is not included here.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 357513375 184 HNCCVCMVRDKGAAFIPCGHT-FCRMCSRELWVSRG-NCPLCNHFILEVLDIF 234
Cdd:cd16518    1 RDCVVCFESEVVAALVPCGHNlFCMECANRICEKSDpECPVCHTPVTQAIRIF 53

RING finger, HC subclass, found in SH3 domain-containing RING finger protein 3 (SH3RF3) and similar proteins; SH3RF3, also known as plenty of SH3s 2 (POSH2) or SH3 multiple domains protein 4 (SH3MD4), is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in a screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating c-Jun N-terminal kinase (JNK) mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1. Both contain an N-terminal C3HC4-type RING-HC finger responsible for the E3 ligase activity and four Src Homology 3 (SH3) domains, which are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs.

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gi 357513375 186 CCVCMVR-DKGAAFIPCGHTFCRMCSRELWVSRGN--CPLC 223
Cdd:cd16750    5 CSVCLERlDTTSKVLPCQHTFCRRCLESIVSSRKElrCPEC 45

zinc finger of C3HC4-type, RING; This is a family of primate-specific Ret finger protein-like (RFPL) zinc-fingers of the C3HC4 type. Ret finger protein-like proteins are primate-specific target genes of Pax6, a key transcription factor for pancreas, eye and neocortex development. This domain is likely to be DNA-binding. This zinc-finger domain together with the RDM domain, pfam11002, forms a large zinc-finger structure of the RING/U-Box superfamily. RING-containing proteins are known to exert an E3 ubiquitin protein ligase activity with the zinc-finger structure being mandatory for binding to the E2 ubiquitin-conjugating enzyme.

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gi 357513375  186 CCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGN----CPLC 223
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQKEPDGesllCPQC 42

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.

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gi 357513375 183 EHNCCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGN----CPLC 223
Cdd:cd16597    5 ELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQHGseysCPQC 49

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.

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gi 357513375 185 NCCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGNCPLC 223
Cdd:cd16561    4 ECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMSCPLC 42

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.

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gi 357513375 183 EHNCCVCMVRDKGAAFIPCGHTFCRMCSRELWVSRGN---CPLC 223
Cdd:cd16594    5 ELTCPICLDYFTDPVTLDCGHSFCRACIARCWEEPETsasCPQC 48

RING finger, HC subclass, found in Caenorhabditis elegans BRCA1-associated RING domain protein 1 (CeBARD1) and similar proteins; CeBARD1, also called Ce-BRD-1, Cebrd-1, or RING-type E3 ubiquitin transferase BARD1, is a constituent of the CeBCD complex that possesses E3 ubiquitin-protein ligase activity. It plays a role in triggering cellular responses at damage sites in response to DNA damage that may be induced by ionizing radiation. It protects against chromosome non-disjunction and nuclear fragmentation during meiotic double-strand break repair to ensure sister chromatid recombination and aid chromosome stability. CeBARD1 contains a typical C3HC4-type RING-HC finger.

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gi 357513375 201 CGHTFCRMCSRELWVSRGNCPLC 223
Cdd:cd23143   20 CGHIYCWECFTEFIEKRHMCPSC 42

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

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gi 357513375 185 NCCVCMVR-DKGAAFI-PCGHTFCRMCSRElWVSRGN-CPLCNH 225
Cdd:cd16574    3 SCPICLDRfENEKAFLdGCFHAFCFTCILE-WSKVKNeCPLCKQ 45