Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of fold. The vWA domain, since its discovery, has drawn great interest because of its widespread occurrence and its involvement in a wide variety of important cellular functions. These include basal membrane formation, cell migration, cell differentiation, adhesion, haemostasis, signaling, chromosomal stability, malignant transformation and in immune defenses In integrins these domains form heterodimers while in vWF it forms multimers. There are different interaction surfaces of this domain as seen by the various molecules it complexes with. Ligand binding in most cases is mediated by the presence of a metal ion dependent adhesion site termed as the MIDAS motif that is a characteristic feature of most, if not all A domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400  99 ISDDYSSLEQVT----------EALARAGLESsNLIVGIDFTKSNEWTGarsfNRKSLHFIGSS-PNPYEQAITIIGRTL 167
Cdd:cd01459   1 IKKVYKSSGEVTltdcrvqptfLDYRSAGLES-NLIVAIDFTKSNGWPG----EKRSLHYISPGrLNPYQKAIRIVGEVL 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 168 AAFDEDNLIPCYGFGDASTHDQDVFSFN---SEDRFCNGFEEVLSRYKEIVPQLKLAGPTSFAPIIDMAMTIVEQS--GG 242
Cdd:cd01459  76 QPYDSDKLIPAFGFGAIVTKDQSVFSFFpgySESPECQGFEGVLRAYREALPNVSLSGPTNFAPVIRAAANIAKASnsQS 155

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 243 QYHVLVIIADGQVTRSVDtengqlspqeqkTVDAIVQASKLPLSIVLVGVGDGPWDMMREFDD-------NIPARAFDNF 315
Cdd:cd01459 156 KYHILLIITDGEITDMNE------------TIKAIVEASKYPLSIVIVGVGDGPFDAMERLDDddglessDGRIATRDIV 223

                       250       260       270
                ....*....|....*....|....*....|....
gi 15241400 316 QFVNFTEIMAKNKaqsLKETEFALSALMEIPQQY 349
Cdd:cd01459 224 QFVPFTEFMSNAG---NPEAALATAALAEIPSQL 254

VWA Copine: Copines are phospholipid-binding proteins originally identified in paramecium. They are found in human and orthologues have been found in C. elegans and Arabidopsis Thaliana. None have been found in D. Melanogaster or S. Cereviciae. Phylogenetic distribution suggests that copines have been lost in some eukaryotes. No functional properties have been assigned to the VWA domains present in copines. The members of this subgroup contain a functional MIDAS motif based on their preferential binding to magnesium and manganese. However, the MIDAS motif is not totally conserved, in most cases the MIDAS consists of the sequence DxTxS instead of the motif DxSxS that is found in most cases. The C2 domains present in copines mediate phospholipid binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400  99 ISDDYSSLEQVT----------EALARAGLESsNLIVGIDFTKSNEWTGarsfNRKSLHFIGSS-PNPYEQAITIIGRTL 167
Cdd:cd01459   1 IKKVYKSSGEVTltdcrvqptfLDYRSAGLES-NLIVAIDFTKSNGWPG----EKRSLHYISPGrLNPYQKAIRIVGEVL 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 168 AAFDEDNLIPCYGFGDASTHDQDVFSFN---SEDRFCNGFEEVLSRYKEIVPQLKLAGPTSFAPIIDMAMTIVEQS--GG 242
Cdd:cd01459  76 QPYDSDKLIPAFGFGAIVTKDQSVFSFFpgySESPECQGFEGVLRAYREALPNVSLSGPTNFAPVIRAAANIAKASnsQS 155

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 243 QYHVLVIIADGQVTRSVDtengqlspqeqkTVDAIVQASKLPLSIVLVGVGDGPWDMMREFDD-------NIPARAFDNF 315
Cdd:cd01459 156 KYHILLIITDGEITDMNE------------TIKAIVEASKYPLSIVIVGVGDGPFDAMERLDDddglessDGRIATRDIV 223

                       250       260       270
                ....*....|....*....|....*....|....
gi 15241400 316 QFVNFTEIMAKNKaqsLKETEFALSALMEIPQQY 349
Cdd:cd01459 224 QFVPFTEFMSNAG---NPEAALATAALAEIPSQL 254

RING finger, HC subclass, found in RING domain ligase RGLG1, RGLG2 and similar proteins from plant; RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. Members of this subfamily contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 15241400 421 DNQLCPICLSNPKDMAFGCGHQTCCECGPDLQMCPICRAPIQTRIKLY 468
Cdd:cd16729   1 DDQLCPICLSNPKDMAFGCGHQTCCECGQSLTHCPICRQPITTRIKLY 48

von Willebrand factor (vWF) type A domain; VWA domains in extracellular eukaryotic proteins mediate adhesion via metal ion-dependent adhesion sites (MIDAS). Intracellular VWA domains and homologues in prokaryotes have recently been identified. The proposed VWA domains in integrin beta subunits have recently been substantiated using sequence-based methods.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400    152 SPNPYEQAITIIGRTLAAFDEDNLIPCYG---FGDASTHdqdVFSFNSEDRFcngfEEVLSRYKEIVPQLKlaGPTSFAP 228
Cdd:smart00327  13 GGNRFELAKEFVLKLVEQLDIGPDGDRVGlvtFSDDARV---LFPLNDSRSK----DALLEALASLSYKLG--GGTNLGA 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400    229 IIDMAMTIV--EQSGGQY---HVLVIIADGQVTRSvdtengqlspqEQKTVDAIVQASKLPLSIVLVGVG-DGPWDMMRE 302
Cdd:smart00327  84 ALQYALENLfsKSAGSRRgapKVVILITDGESNDG-----------PKDLLKAAKELKRSGVKVFVVGVGnDVDEEELKK 152

                          170       180
                   ....*....|....*....|...
gi 15241400    303 FDD-NIPARAFDNFQFVNFTEIM 324
Cdd:smart00327 153 LASaPGGVYVFLPELLDLLIDLL 175

VWA Copine: Copines are phospholipid-binding proteins originally identified in paramecium. They are found in human and orthologues have been found in C. elegans and Arabidopsis Thaliana. None have been found in D. Melanogaster or S. Cereviciae. Phylogenetic distribution suggests that copines have been lost in some eukaryotes. No functional properties have been assigned to the VWA domains present in copines. The members of this subgroup contain a functional MIDAS motif based on their preferential binding to magnesium and manganese. However, the MIDAS motif is not totally conserved, in most cases the MIDAS consists of the sequence DxTxS instead of the motif DxSxS that is found in most cases. The C2 domains present in copines mediate phospholipid binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400  99 ISDDYSSLEQVT----------EALARAGLESsNLIVGIDFTKSNEWTGarsfNRKSLHFIGSS-PNPYEQAITIIGRTL 167
Cdd:cd01459   1 IKKVYKSSGEVTltdcrvqptfLDYRSAGLES-NLIVAIDFTKSNGWPG----EKRSLHYISPGrLNPYQKAIRIVGEVL 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 168 AAFDEDNLIPCYGFGDASTHDQDVFSFN---SEDRFCNGFEEVLSRYKEIVPQLKLAGPTSFAPIIDMAMTIVEQS--GG 242
Cdd:cd01459  76 QPYDSDKLIPAFGFGAIVTKDQSVFSFFpgySESPECQGFEGVLRAYREALPNVSLSGPTNFAPVIRAAANIAKASnsQS 155

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15241400 243 QYHVLVIIADGQVTRSVDtengqlspqeqkTVDAIVQASKLPLSIVLVGVGDGPWDMMREFDD-------NIPARAFDNF 315
Cdd:cd01459 156 KYHILLIITDGEITDMNE------------TIKAIVEASKYPLSIVIVGVGDGPFDAMERLDDddglessDGRIATRDIV 223

                       250       260       270
                ....*....|....*....|....*....|....
gi 15241400 316 QFVNFTEIMAKNKaqsLKETEFALSALMEIPQQY 349
Cdd:cd01459 224 QFVPFTEFMSNAG---NPEAALATAALAEIPSQL 254

RING finger, HC subclass, found in RING domain ligase RGLG1, RGLG2 and similar proteins from plant; RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. Members of this subfamily contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 15241400 421 DNQLCPICLSNPKDMAFGCGHQTCCECGPDLQMCPICRAPIQTRIKLY 468
Cdd:cd16729   1 DDQLCPICLSNPKDMAFGCGHQTCCECGQSLTHCPICRQPITTRIKLY 48

third RING finger, HC subclass, found in mind bomb 1 (MIB1) and similar proteins; MIB1, also known as DAPK-interacting protein 1 (DIP-1) or zinc finger ZZ type with ankyrin repeat domain protein 2, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands, and thus plays an essential role in controlling metazoan development by Notch signaling. It is also involved in Wnt/beta-catenin signaling and nuclear factor (NF)-kappaB signaling, and has been implicated in innate immunity, neuronal function, genomic stability, and cell death. MIB1 contains an MZM region with two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region consisting of three C3HC4-type RING-HC fingers. This model corresponds to the third RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15241400 424 LCPICLSNPKDMAFGCGHQTCCECGPDLQMCPICRAPIQTRIKLY 468
Cdd:cd16727   2 MCPVCLDRLKNMIFLCGHGTCQLCGDRMSECPICRKAIEKRILLY 46

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 15241400   421 DNQLCPICLSNPKDMAFG-CGHQTCC-ECGPDLQM----CPICRAPIQTR 464
Cdd:pfam13920   1 EDLLCVICLDRPRNVVLLpCGHLCLCeECAERLLRkkkkCPICRQPIESV 50

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein NEURL1A, NEURL1B, and similar proteins; This subfamily includes Drosophila neuralized (D-neu) protein, and its two mammalian homologs, NEURL1A and NEURL1B. D-neu is a regulator of the developmentally important Notch signaling pathway. NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of D-neu. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in medulloblastoma. NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is another mammalian homolog of D-neu protein. It functions as an E3 ubiquitin-protein ligase that interacts with and ubiquitinates Delta. Thus, it plays a role in the endocytic pathways for Notch signaling by working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. Members of this subfamily contain two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger 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 15241400 425 CPICLSNPKDMAF-GCGHQTCC-ECGPDLQM----CPICRAPIQTRIKLY 468
Cdd:cd16647   4 CVICYERPVDTVLyRCGHMCMCyDCALQLKRrggsCPICRAPIKDVIKIY 53

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
                ....*....|....*....|....*....|....*....|....*....
gi 15241400 425 CPICLSNPKDMAF-GCGHQTCC-EC---GPDLQMCPICRAPIQTRIKLY 468
Cdd:cd16648   4 CVICLSNPRSCVFlECGHVCSCiECyeaLPSPKKCPICRSFIKRVVPLY 52

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
                ....*....|....*....|....*....|....*....
gi 15241400 423 QLCPICLSNPKDMAF-GCGHQTCC-ECGPDLQMCPICRA 459
Cdd:cd16510   2 KLCKICMDREVNIVFlPCGHLVTCaQCAASLRKCPICRT 40

RING finger, HC subclass, found in leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) and similar proteins; LRSAM1, also known as Tsg101-associated ligase (TAL), or RIFLE, is an E3 ubiquitin-protein ligase that physically associates with, and selectively ubiquitylates, Tsg101, an E2-like molecule that regulates vesicular trafficking processes in yeast and mammals. It regulates a Tsg101-associated complex responsible for the sorting of cargo into cytoplasm-containing vesicles that bud at the multivesicular body and at the plasma membrane. LRSAM1 is a multidomain protein containing an N-terminal leucine-rich repeat (LRR), followed by several recognizable motifs, including an ezrin-radixin-moezin (ERM) domain, a coiled-coil (CC) region, a SAM domain, and a C-terminal C3HC4-type RING-HC finger domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15241400 425 CPICLSNPKDMAF-GCGHQTCCE-CGPDLQMCPICRAPIQTRIKL 467
Cdd:cd16515   4 CVVCMDAESQVIFlPCGHVCCCQtCSSSLSTCPLCRADITQRVRI 48

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein CARP-1, CARP-2 and similar proteins; The CARP subfamily includes CARP-1 and CARP-2 proteins, both of which are E3 ubiquitin ligases that ubiquitinate apical caspases and target them for proteasome-mediated degradation. As a novel group of caspase regulators with a FYVE-type zinc finger domain, they do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8, and caspase 10. Moreover, they stabilize MDM2 by inhibiting MDM2 self-ubiquitination, as well as by targeting 14-3-3sigma for degradation. They work together with MDM2 to enhance p53 degradation, thereby inhibiting p53-mediated cell death. CARPs contain an N-terminal FYVE-like domain that can serve as a membrane-targeting or endosome localizing signal and a C-terminal C3HC4-type RING-HC finger domain.

                        10        20        30
                ....*....|....*....|....*....|....*..
gi 15241400 424 LCPICLSNPKDMAF-GCGHQTCC-ECGPDLQMCPICR 458
Cdd:cd16500   2 LCKICMDAAIDCVLlECGHMVTCtDCGKKLSECPICR 38

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 2 (CARP-2) and similar proteins; CARP-2, also known as rififylin, caspase regulator CARP2, FYVE-RING finger protein Sakura (Fring), RING finger and FYVE-like domain-containing protein 1, RING finger protein 189 (RNF189), or RING finger protein 34-like, is an endosome-associated E3 ubiquitin-protein ligase that targets internalized receptor interacting kinase (RIP) for proteasome-mediated degradation. It acts as a negative regulator of tumor necrosis factor (TNF)-induced nuclear factor (NF)-kappaB activation. It also regulates the p53 signaling pathway by degrading 14-3-3sigma and stabilizing MDM2. As a caspase regulator, CARP2 does not localize to membranes in the cell and is involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10. CARP2 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 15241400 421 DNQLCPICLSNPKD-MAFGCGHQ-TCCECGPDLQMCPICR 458
Cdd:cd16707   1 DENLCKICMDSPIDcVLLECGHMvTCTKCGKRMSECPICR 40

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 15241400 425 CPICLSNPKDMAF-GCGHQTCCEC-----GPDLQMCPIC 457
Cdd:cd16449   3 CPICLERLKDPVLlPCGHVFCRECirrllESGSIKCPIC 41

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1A (NEURL1A) and similar proteins; NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of the Drosophila neuralized (D-neu) protein. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in the medulloblastoma. NEURL1A contains two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger 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 15241400 425 CPICLSNPKD-MAFGCGHQTCC-ECGPDLQM-----CPICRAPIQTRIKLY 468
Cdd:cd16785   7 CTICYENAVDtVIYTCGHMCLCyACGLRLKKmlnacCPICRRAIKDIIKTY 57

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
                ....*....|....*....|....*....|....*....|....*...
gi 15241400 423 QLCPICLSNPKDMAF-GCGHQ-TCCECGPDLQMCPICRAPIQTRIKLY 468
Cdd:cd16714  15 KLCKICMDRNISIVFiPCGHLvTCKQCAEALDKCPICCTVITFKQKIF 62

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).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 15241400 423 QLCPICLSNPKD-MAF--GCGHQTCCECgpdLQ-------MCPICRAPI 461
Cdd:cd16574   2 SSCPICLDRFENeKAFldGCFHAFCFTC---ILewskvknECPLCKQPF 47

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 1 (CARP1) and similar proteins; CARP1, also known as caspase regulator CARP1, FYVE-RING finger protein Momo, RING finger homologous to inhibitor of apoptosis protein (RFI), RING finger protein 34 (RNF34), or RING finger protein RIFF, is a nuclear protein that functions as a specific E3 ubiquitin ligase for the transcriptional coactivator PGC-1alpha, a master regulator of energy metabolism and adaptive thermogenesis in the brown fat cell which negatively regulates brown fat cell metabolism. It is preferentially expressed in esophageal, gastric, and colorectal cancers, suggesting a possible association with the development of digestive tract cancers. It regulates the p53 signaling pathway by degrading 14-3-3 sigma and stabilizing MDM2. CARP1 does not localize to membranes in the cell and is involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10. CARP1 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 15241400 421 DNQLCPICLSNPKD-MAFGCGHQ-TCCECGPDLQMCPICR 458
Cdd:cd16706   3 DDNLCRICMDAVIDcVLLECGHMvTCTKCGKRMSECPICR 42

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
                ....*....|....*....|....*....|....*....|...
gi 15241400 425 CPICLSNPKD--MAFGCGHQTCCEC----GPDLQMCPICRAPI 461
Cdd:cd23130   3 CPICLDDPEDeaITLPCLHQFCYTCilrwLQTSPTCPLCKTPV 45

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 15241400 421 DNQLCPICLSNPKD-MAFGCGHQTCCEC----GPDLQMCPICRA 459
Cdd:cd16561   1 GEQECSICLEDLNDpVKLPCDHVFCEECirqwLPGQMSCPLCRT 44

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 15241400 421 DNQLCPICLSNPKD-MAFGCGHQTCCEC------GPDLQMCPICRAP 460
Cdd:cd16608   5 DELLCSICLSIYQDpVSLGCEHYFCRQCitehwsRSEHRDCPECRRT 51

Modified RING finger, HC subclass (C3HC5-type), found in cell growth regulator with RING finger domain protein 1 (CGRRF1) and similar proteins; CGRRF1, also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. CGRRF1 contains a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 15241400 423 QLCPICLSNPKDMAF-GCGHQTCC-ECGPDLQMCPICR 458
Cdd:cd16787   1 KDCVVCQNAPVNRVLlPCRHACVCdECFKRLQRCPMCR 38

RING finger, HC subclass, found in RING finger protein 185 (RNF185) and similar proteins; RNF185 is an E3 ubiquitin-protein ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR). It controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical ERAD model substrates. It also negatively regulates osteogenic differentiation by targeting dishevelled2 (Dvl2), a key mediator of the Wnt signaling pathway, for degradation. Moreover, RNF185 regulates selective mitochondrial autophagy through interaction with the Bcl-2 family protein BNIP1. It also plays an important role in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. RNF185 contains a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15241400 425 CPICLSNPKDMAFG-CGHQTCCEC-------GPDLQMCPICRAPI 461
Cdd:cd16744   3 CNICLDTAKDAVVSlCGHLFCWPClhqwletRPNRQVCPVCKAGI 47

RING finger, HC subclass, found in tripartite motif-containing protein 26 (TRIM26) and similar proteins; TRIM26, also known as acid finger protein (AFP), RING finger protein 95 (RNF95), or zinc finger protein 173 (ZNF173), is an E3 ubiquitin-protein ligase that negatively regulates interferon-beta production and antiviral response through polyubiquitination and degradation of nuclear transcription factor IRF3. It functions as an important regulator for RNA virus-triggered innate immune response by bridging TBK1 to NEMO (NF-kappaB essential modulator, also known as IKKgamma) and mediating TBK1 activation. It also acts as a novel tumor suppressor of hepatocellular carcinoma by regulating cancer cell proliferation, colony forming ability, migration, and invasion. TRIM26 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
                ....*....|....*....|....*....|....*....|....*...
gi 15241400 425 CPICLSNPKD-MAFGCGHQTCCEC---------GPDLQMCPICRAPIQ 462
Cdd:cd16598   7 CSICLDYLRDpVTIDCGHNFCRSCitdycpisgGHERPVCPLCRKPFK 54

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-b and similar proteins; Cbl-b, also known as Casitas B-lineage lymphoma proto-oncogene b, RING finger protein 56 (RNF56), SH3-binding protein Cbl-b, or signal transduction protein Cbl-b, has been identified as a regulator of antigen-specific, T cell-intrinsic, peripheral immune tolerance, a state also known as clonal anergy. It may inhibit activation of the p85 subunit of phosphoinositide 3-kinase (PI3K), protein kinase C-theta (PKC-theta), and phospholipase C-gamma1 (PLC-gamma1) and negatively regulates T-cell receptor-induced transcription factor nuclear factor kappaB (NF-kappaB) activation. In addition, Cbl-b may target multiple signaling molecules involved in transforming growth factor (TGF)-beta-mediated transactivation pathways. Cbl-b contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline rich domain, a nuclear localization signal, a C3HC4-type RING-HC finger and an ubiquitin-associated (UBA) domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 15241400 423 QLCPICLSNPKDMAF-GCGHQTCCEC-----GPDLQMCPICRAPIQ 462
Cdd:cd16709  21 QLCKICAENDKDVKIePCGHLMCTSCltawqESDGQGCPFCRCEIK 66

RING finger, HC subclass, found in RING finger protein 166 (RNF166) and similar proteins; RNF166 is encoded by the gene RNF166 targeted by thyroid hormone receptor alpha1 (TRalpha1), which is important in brain development. It plays an important role in RNA virus-induced interferon-beta production by enhancing the ubiquitination of TRAF3 and TRAF6. RNF166, together with three closely related proteins: RNF114, RNF125 and RNF138, 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 15241400 425 CPICLS---NPKDMAfGCGHQTCCEC-GPDLQ----MCPICRAP 460
Cdd:cd16549   4 CPICLEvyhKPVVIT-SCGHTFCGEClQPCLQvaspLCPLCRMP 46

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        40
                ....*....|....*....|....*....|....*....|...
gi 15241400 425 CPICLSNPKD-MAFGCGHQTCCEC----GPDLQMCPICRAPIQ 462
Cdd:cd16527   3 CSLCLEERRHpTATPCGHLFCWSCitewCNEKPECPLCREPFQ 45

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 15241400 425 CPICLSNPKD-MAFGCGHQTCCEC------GPDLQM-CPICRAPIQTR 464
Cdd:cd16594   8 CPICLDYFTDpVTLDCGHSFCRACiarcweEPETSAsCPQCRETCPQR 55

RING finger, HC subclass, found in two RING fingers and DRIL [double RING finger linked] 1 (TRIAD1); TRIAD1, also known as ariadne-2 (ARI-2), protein ariadne-2 homolog, Ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2), or UbcM4-interacting protein 48, is an RBR-type E3 ubiquitin-protein ligase that catalyzes the formation of polyubiquitin chains linked via lysine-48, as well as lysine-63 residues. Its auto-ubiquitylation can be catalyzed by the E2 conjugating enzyme UBCH7. TRIAD1 has been implicated in hematopoiesis, specifically in myelopoiesis, as well as in embryogenesis. It functions as a regulator of endosomal transport and is required for the proper function of multivesicular bodies. It also acts as a novel ubiquitination target for proteasome-dependent degradation by murine double minute 2 (MDM2). As a proapoptotic protein, TRIAD1 promotes p53 activation, and inhibits MDM2-mediated p53 ubiquitination and degradation. Furthermore, TRIAD1 can inhibit the ubiquitination and proteasomal degradation of growth factor independence 1 (Gfi1), a transcriptional repressor essential for the function and development of many different hematopoietic lineages. TRIAD1 contains an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C3HC4-type RING-HC finger required for RBR-mediated ubiquitination.

                        10        20
                ....*....|....*....|....*.
gi 15241400 425 CPICLSN-PKDMAFG--CGHQTCCEC 447
Cdd:cd16773   3 CGVCCEDvPKDELFSlaCGHYFCNDC 28

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also known as Casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55 (RNF55), or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinase signaling. It contains a tyrosine kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB is responsible for the interactions with many tyrosine kinases, such as the colony-stimulating factor-1 (CSF-1) receptor, Syk/ZAP-70, and Src-family of protein tyrosine kinases. The proline-rich domain can recruit proteins with a SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through the RING-HC finger.

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                ....*....|....*....|....*....|....*....|....*.
gi 15241400 423 QLCPICLSNPKDMAFG-CGHQTCCEC-----GPDLQMCPICRAPIQ 462
Cdd:cd16708  22 QLCKICAENDKDVKIEpCGHLMCTSCltswqESEGQGCPFCRCEIK 67

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        50
                ....*....|....*....|....*....|....*....|....*....|
gi 15241400 421 DNQLCPICLSNPKDMAFG-CGHQTCCEC-----GPDLQMCPICRAPIQTR 464
Cdd:cd16509   2 SDEECAICLDSLTNPVITpCAHVFCRRCiceviQREKAKCPMCRAPLSAS 51

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 15241400 425 CPIClSNPKDMAFG---CGHQTCCECGPDLQ----MCPICRAPI 461
Cdd:cd23143   4 CVIC-SEPQIDTFLlssCGHIYCWECFTEFIekrhMCPSCRFPL 46