FYVE domain like superfamily; FYVE domain is a 60-80 residue double zinc finger motif-containing module named after the four proteins, Fab1, YOTB, Vac1, and EEA1. The canonical FYVE domains are distinguished from other zinc fingers by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P, also termed PI3P)-binding site. They are found in many membrane trafficking regulators, including EEA1, Hrs, Vac1p, Vps27p, and FENS-1, which locate to early endosomes, specifically bind PtdIns3P, and play important roles in vesicular traffic and in signal transduction. Some proteins, such as rabphilin-3A and alpha-Rab3-interacting molecules (RIMs), are also involved in membrane trafficking and bind to members of the Rab subfamily of GTP hydrolases. However, they contain FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences. At this point, they may not bind to phosphoinositides. In addition, this superfamily also contains the third group of proteins, caspase-associated ring proteins CARP1 and CARP2. 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, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains. The FYVE domain is structurally similar to the RING domain and the PHD finger. This superfamily also includes ADDz zinc finger domain, which is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1712927960  59 GQLCKACGLAFSVFRRKHICCDCKKSFCALCSVLQENLRCCTTCHLL 105
Cdd:cd15769     1 NIVCKACGLAFSVFRKKHVCCDCKKDFCSVCSVLQENLRRCSTCHLL 47

FYVE-like domain found in caspase regulator CARP1 and similar proteins; CARP1, also termed E3 ubiquitin-protein ligase RNF34, or caspases-8 and -10-associated RING finger protein 1, or FYVE-RING finger protein Momo, or RING finger homologous to inhibitor of apoptosis protein (RFI), or RING finger protein 34, 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, and negatively regulates brown fat cell metabolism. It is preferentially expressed in esophageal, gastric and colorectal cancers, suggesting a possible association with the development of the digestive tract cancers. It regulates the p53 signaling pathway through 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, which are distinguished from other FYVE-type proteins. Moreover, CARP1 has an altered sequence in the basic ligand binding patch and lack the WxxD (x for any residue) motif that is conserved only in phosphoinositide binding FYVE domains. Thus it belongs to a family of unique FYVE-type domains called FYVE-like domains. In addition to the N-terminal FYVE-like domain, CARP1 harbors a C-terminal RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1712927960  59 GQLCKACGLAFSVFRRKHICCDCKKSFCALCSVLQENLRCCTTCHLL 105
Cdd:cd15769     1 NIVCKACGLAFSVFRKKHVCCDCKKDFCSVCSVLQENLRRCSTCHLL 47

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1712927960 331 RENQQNRKSMENVSITADgvKAQLASDENLCRICMDAIIDCVLLECGHMvTCTKCGKRM------SECPICR 396
Cdd:COG5236    36 RKQKKNNLSAEPNLTTSS--ADDTDEENMNCQICAGSTTYSARYPCGHQ-ICHACAVRLralymqKGCPLCR 104

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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1712927960 357 DENLCRICMDAIIDCVLLECGHMVTCTKCGKRMSECPICRQYVVRAVHVF 406
Cdd:cd16707     1 DENLCKICMDSPIDCVLLECGHMVTCTKCGKRMSECPICRQYVIRAVHVF 50

FYVE-like domain found in caspase regulator CARP1 and similar proteins; CARP1, also termed E3 ubiquitin-protein ligase RNF34, or caspases-8 and -10-associated RING finger protein 1, or FYVE-RING finger protein Momo, or RING finger homologous to inhibitor of apoptosis protein (RFI), or RING finger protein 34, 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, and negatively regulates brown fat cell metabolism. It is preferentially expressed in esophageal, gastric and colorectal cancers, suggesting a possible association with the development of the digestive tract cancers. It regulates the p53 signaling pathway through 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, which are distinguished from other FYVE-type proteins. Moreover, CARP1 has an altered sequence in the basic ligand binding patch and lack the WxxD (x for any residue) motif that is conserved only in phosphoinositide binding FYVE domains. Thus it belongs to a family of unique FYVE-type domains called FYVE-like domains. In addition to the N-terminal FYVE-like domain, CARP1 harbors a C-terminal RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1712927960  59 GQLCKACGLAFSVFRRKHICCDCKKSFCALCSVLQENLRCCTTCHLL 105
Cdd:cd15769     1 NIVCKACGLAFSVFRKKHVCCDCKKDFCSVCSVLQENLRRCSTCHLL 47

FYVE-like domain found in caspase-associated ring proteins, CARP1 and CARP2; CARP1 and CARP2 are a novel group of caspase regulators by the presence of 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, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD (x for any residue) motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1712927960  62 CKACGLAFSVFRRKHICCDCKKSFCALCSVLQEN-LRCCTTCHLL 105
Cdd:cd15750     3 CESCGAKFSVFKRKRTCADCKRYFCSNCLSKEERgRRRCRRCRAL 47

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 1712927960 357 DENLCRICMDAIIDCVLLECGHMVTCTKCGKRMSECPICRQYVVRAVHVFKS 408
Cdd:cd16714    13 EEKLCKICMDRNISIVFIPCGHLVTCKQCAEALDKCPICCTVITFKQKIFMS 64

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 1712927960 361 CRICMDAIIDCVLLECGHMVTCTKCGKRMSE----CPICRQYVVRAVHVF 406
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        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1712927960 358 ENLCRICMDAIIDCVLLECGHMVTCTKCGKRMSE---CPICRQYVVRAVHVF 406
Cdd:cd16648     1 DNACVICLSNPRSCVFLECGHVCSCIECYEALPSpkkCPICRSFIKRVVPLY 52

RING finger, HC subclass, found in mind bomb MIB1, MIB2, RGLG1, RGLG2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of 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, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the third RING-HC finger of MIB1, as well as the second RING-HC finger of MIB2. In addition to MIB1 and MIB2, the RING-HC fingers of RING domain ligase RGLG1, RGLG2 and similar proteins from plant are also included in this model. 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. All RGLG proteins contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1712927960 360 LCRICMDAIIDCVLLeCGHMvTCTKCGKRMSECPICRQ 397
Cdd:cd16520     2 LCPICMERKKNVVFL-CGHG-TCQKCAEKLKKCPICRK 37

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 1712927960 359 NLCRICMDAIIDCVLLeCGHMvTCTKCGKRMSECPICRQYVVRAVHVF 406
Cdd:cd16727     1 TMCPVCLDRLKNMIFL-CGHG-TCQLCGDRMSECPICRKAIEKRILLY 46

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 1712927960 361 CRICMDAIIDCVLLECGHMVTCTKCGKRMSE-----CPICRQYVVRAVHVFKS 408
Cdd:cd16785     7 CTICYENAVDTVIYTCGHMCLCYACGLRLKKmlnacCPICRRAIKDIIKTYRS 59

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1B (NEURL1B); NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is a mammalian homolog of the Drosophila neuralized (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 through working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. NEURL1B 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 1712927960 361 CRICMDAIIDCVLLECGHMVTCTKCGKRMSE-----CPICRQYVVRAVHVFKS 408
Cdd:cd16786     5 CTVCFDSEVDTVIYTCGHMCLCNSCGLKLKRqinacCPICRRVIKDVIKIYRP 57

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1712927960 331 RENQQNRKSMENVSITADgvKAQLASDENLCRICMDAIIDCVLLECGHMvTCTKCGKRM------SECPICR 396
Cdd:COG5236    36 RKQKKNNLSAEPNLTTSS--ADDTDEENMNCQICAGSTTYSARYPCGHQ-ICHACAVRLralymqKGCPLCR 104

RING finger, HC subclass, found in RNA-binding protein MEX3B; MEX3B, also known as RING finger and KH domain-containing protein 3 (RKHD3), or RING finger protein 195 (RNF195), is an RNA-binding phosphoprotein that localizes in P-bodies and stress granules, which are two structures involved in the storage and turnover of mRNAs. It regulates the spatial organization of the Rap1 pathway that orchestrates Sertoli cell functions. It has a 3' long conserved untranslated region (3'LCU)-mediated fine-tuning system for mRNA regulation in early vertebrate development such as anteroposterior (AP) patterning and signal transduction. MEX3B contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3B shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1712927960 361 CRICMDAIIDCVLLECGHMVTCTKCGKRMSE-----CPICRQYVVRAVHVF 406
Cdd:cd16721     7 CSICFESEVIAALVPCGHNLFCMECANRICEknepqCPVCHAAVTQAIRIF 57

FYVE domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY1 contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1712927960  62 CKACGLAFSVFRRKHICCDCKKSFCALCSVLQENL-------RCCTTCHLL 105
Cdd:cd15758    15 CKQCEKEFSISRRKHHCRNCGHIFCNTCSSNELALpsypkpvRVCDSCHTL 65

FYVE domain found in RUN and FYVE domain-containing protein RUFY1, RUFY2 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1 and RUFY2. RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. Both RUFY1 and RUFY2 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1712927960  62 CKACGLAFSVFRRKHICCDCKKSFCALCSVLQENL-------RCCTTCH 103
Cdd:cd15721    10 CQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTMPLpssakpvRVCDTCY 58

Modified RING finger, HC subclass (C3HC5-type), found in mahogunin RING finger protein 1 (MGRN1), RING finger protein 157 (RNF157) and similar proteins; MGRN1, also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signaling by competition with Galphas, suggesting a novel pathway for melanocortin signaling from the cell surface to the nucleus. MGRN1 also interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase mahogunin ring finger-1 (MGRN1). In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis. Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterized region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger. The C3HC5-type RING-HC finger 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        40
                  ....*....|....*....|....*....|....*....|..
gi 1712927960 359 NLCRICMDAIIDCVLLECGHMVTCTKCGKRM----SECPICR 396
Cdd:cd16789     1 SECVICLSDPRDTAVLPCRHLCLCSDCAEVLryqsNKCPICR 42

FYVE domain found in lateral signaling target protein 2 homolog (Lst2) and similar proteins; Lst2, also termed zinc finger FYVE domain-containing protein 28, is a monoubiquitinylated phosphoprotein that functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling. Unlike other FYVE domain-containing proteins, Lst2 displays primarily non-endosomal localization. Its endosomal localization is regulated by monoubiquitinylation. Lst2 physically binds Trim3, also known as BERP or RNF22, which is a coordinator of endosomal trafficking and interacts with Hrs and a complex that biases cargo recycling.

                          10        20
                  ....*....|....*....|....*....
gi 1712927960  62 CKACGLAFSVFRRKHICCDCKKSFCALCS 90
Cdd:cd15731    14 CMACSAPFTVLRRRHHCRNCGKIFCSRCS 42

Modified RING finger, HC subclass (C3HC5-type), found in RING finger proteins, RNF26, RNF197 (CGRRF1), RNF156 (MGRN1), RNF157 and similar proteins; This subfamily corresponds to a group of RING finger proteins containing a 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. Cell growth regulator with RING finger domain protein 1 (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. RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction. Mahogunin ring finger-1 (MGRN1), also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase MGRN1. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1712927960 359 NLCRICMDAIIDCVLLECGHMVTCTKCGKRMSE--CPICR 396
Cdd:cd16649     1 GLCVVCLENPASVLLLPCRHLCLCEVCAKGLRGktCPICR 40

FYVE domain found in WD40 repeat and FYVE domain-containing protein 3 (WDFY3) and similar proteins; WDFY3, also termed autophagy-linked FYVE protein (Alfy), is a ubiquitously expressed phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein required for selective macroautophagic degradation of aggregated proteins. It regulates the protein degradation through the direct interaction with the autophagy protein Atg5. Moreover, WDFY3 acts as a scaffold that bridges its cargo to the macroautophagic machinery via the creation of a greater complex with Atg12, Atg16L, and LC3. It also functionally associates with sequestosome-1/p62 (SQSTM1) in osteoclasts. WDFY3 shuttles between the nucleus and cytoplasm. It predominantly localizes to the nucleus and nuclear membrane under basal conditions, but is recruited to cytoplasmic ubiquitin-positive protein aggregates under stress conditions. WDFY3 contains a PH-BEACH domain assemblage, five WD40 repeats and a PtdIns3P-binding FYVE domain.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1712927960  59 GQLCKACGLAFSVFRRKHICCDCKKSFCALCS 90
Cdd:cd15719     9 GDSCTGCSVRFSLTERRHHCRNCGQLFCSKCS 40

FYVE domain found in FYVE finger-containing Rab5 effector protein rabenosyn-5 (Rbsn-5) and similar proteins; Rbsn-5, also termed zinc finger FYVE domain-containing protein 20, is a novel Rab5 effector that is complexed to the Sec1-like protein VPS45 and recruited in a phosphatidylinositol-3-kinase-dependent fashion to early endosomes. It also binds to Rab4 and EHD1/RME-1, two regulators of the recycling route, and is involved in cargo recycling to the plasma membrane. Moreover, Rbsn-5 regulates endocytosis at the apical side of the wing epithelium and plays a role of the apical endocytic trafficking of Fmi in the establishment of planar cell polarity (PCP).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1712927960  60 QLCKACGLAFSVFRRKHICCDCKKSFCALCSV-LQENLRCCTTC 102
Cdd:cd15716    11 PFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQfLPLHIRCCHHC 54

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 1712927960 357 DENLCRICMDAIIDCVLLECGHMVtCTKC------GKRMSECPICR 396
Cdd:cd23132     1 EEFLCCICLDLLYKPVVLECGHVF-CFWCvhrcmnGYDESHCPLCR 45

FYVE domain found in myotubularin-related protein 4 (MTMR4) and similar proteins; MTMR4, also termed FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2), or zinc finger FYVE domain-containing protein 11, is an dual specificity protein phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). It is localizes to early endosomes, as well as to Rab11- and Sec15-positive recycling endosomes, and regulates sorting from early endosomes. Moreover, MTMR4 is preferentially associated with and dephosphorylated the activated regulatory Smad proteins (R-Smads) in cytoplasm to keep transforming growth factor (TGF) beta signaling in homeostasis. It also functions as an essential negative modulator for the homeostasis of bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signaling. In addition, MTMR4 acts as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4) and may play a role in the biological process of muscle breakdown. MTMR4 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain.

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1712927960  62 CKACGLAFSVFRRKHICCDCKKSFCALCS-----VLQENL----RCCTTCH 103
Cdd:cd15733    10 CFGCDCEFWLAKRKHHCRNCGNVFCADCSnyklpIPDEQLydpvRVCNSCY 60

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.

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1712927960 361 CRICMDAIIDCVLLECGHMVTCTKCGKRM-----SECPICRQYVVRAVHVF 406
Cdd:cd16518     3 CVVCFESEVVAALVPCGHNLFCMECANRIceksdPECPVCHTPVTQAIRIF 53

FYVE domain found in hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also termed protein pp110, is a tyrosine phosphorylated protein that plays an important role in the signaling pathway of HGF. It is localized to early endosomes and an essential component of the endosomal sorting and trafficking machinery. Hrs interacts with hypertonia-associated protein Trak1, a novel regulator of endosome-to-lysosome trafficking. It can also forms an Hrs/actinin-4/BERP/myosin V protein complex that is required for efficient transferrin receptor (TfR) recycling but not for epidermal growth factor receptor (EGFR) degradation. Moreover, Hrs, together with STAM proteins, STAM1 and STAM2, and EPs15, forms a multivalent ubiquitin-binding complex that sorts ubiquitinated proteins into the multivesicular body pathway, and plays a regulatory role in endocytosis/exocytosis. Furthermore, Hrs functions as an interactor of the neurofibromatosis 2 tumor suppressor protein schwannomin/merlin. It is also involved in the inhibition of citron kinase-mediated HIV-1 budding. Hrs contains a single ubiquitin-interacting motif (UIM) that is crucial for its function in receptor sorting, and a FYVE domain that harbors double Zn2+ binding sites.

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 1712927960  59 GQLCKACGLAFSVFRRKHICCDCKKSFCALCSV---------LQENLRCCTTCH 103
Cdd:cd15720     5 GDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSksstipkfgIEKEVRVCDPCY 58