RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCKGQPLPW 315
Cdd:cd16772    1 KKCIVCQERDRSIVLQPCQHYVLCEHCAASKPECPYCKTKILKW 44

RING finger, HC subclass, found in RING finger protein unkempt-like (UNKL) and similar proteins; UNKL, also known as zinc finger CCCH domain-containing protein 5-like, is a putative E3 ubiquitin-protein ligase that may participate in a protein complex showing an E3 ligase activity regulated by RAC1. It shows high sequence similarity with RING finger protein unkempt (UNK), which is a metazoan-specific zinc finger protein enriched in embryonic brains, and may play a broad regulatory role during the formation of the central nervous system (CNS). UNKL contains several CCCH-type zinc fingers at the N-terminus, and a C3HC4-type RING-HC finger at its C-terminus.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCKGQPLPW 315
Cdd:cd16772    1 KKCIVCQERDRSIVLQPCQHYVLCEHCAASKPECPYCKTKILKW 44

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 672067044  152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADSD-RQLALQRKEEVEAQVKQLQEELE 224
Cdd:COG4913   282 RLWFAQRRLELLEAELEELRAELARLEAELERLEARLDALREELDELEAQiRGNGGDRLEQLEREIERLERELE 355

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 672067044   152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDawQREAQEAKERARVadsdrQLALQRKEEVEAQVKQLQEELEGLG 227
Cdd:TIGR02168  359 ELEELEAELEELESRLEELEEQLETLRSKVA--QLELQIASLNNEI-----ERLEARLERLEDRRERLQQEIEELL 427

RING finger, HC subclass, found in RING finger protein unkempt-like (UNKL) and similar proteins; UNKL, also known as zinc finger CCCH domain-containing protein 5-like, is a putative E3 ubiquitin-protein ligase that may participate in a protein complex showing an E3 ligase activity regulated by RAC1. It shows high sequence similarity with RING finger protein unkempt (UNK), which is a metazoan-specific zinc finger protein enriched in embryonic brains, and may play a broad regulatory role during the formation of the central nervous system (CNS). UNKL contains several CCCH-type zinc fingers at the N-terminus, and a C3HC4-type RING-HC finger at its C-terminus.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCKGQPLPW 315
Cdd:cd16772    1 KKCIVCQERDRSIVLQPCQHYVLCEHCAASKPECPYCKTKILKW 44

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 672067044  272 KQCVACQERAHGTVLRPCQHRVLCEPCA----ASTPECPYCK 309
Cdd:pfam13920   3 LLCVICLDRPRNVVLLPCGHLCLCEECAerllRKKKKCPICR 44

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 672067044 271 AKQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCKG 310
Cdd:cd16510    1 EKLCKICMDREVNIVFLPCGHLVTCAQCAASLRKCPICRT 40

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 672067044  152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADSD-RQLALQRKEEVEAQVKQLQEELE 224
Cdd:COG4913   282 RLWFAQRRLELLEAELEELRAELARLEAELERLEARLDALREELDELEAQiRGNGGDRLEQLEREIERLERELE 355

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 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCK 309
Cdd:cd16787    1 KDCVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 38

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044  153 LARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADSDRQLAlqrkeEVEAQVKQLQEELEGLGLSSlP 232
Cdd:COG4913   612 LAALEAELAELEEELAEAEERLEALEAELDALQERREALQRLAEYSWDEIDVA-----SAEREIAELEAELERLDASS-D 685

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 672067044  233 GLRSLGDISDiplpKLHSLQSQLRLDLEAVDGVIFQLRAKQ 273
Cdd:COG4913   686 DLAALEEQLE----ELEAELEELEEELDELKGEIGRLEKEL 722

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 672067044 152 ELARVRRQLDEAKRKIRQWEE---SWQQVKQACDAWQREAQEAKERARVADSDR-QLALQRKEEVEAQVKQLQEELEGL 226
Cdd:COG4717  140 ELAELPERLEELEERLEELREleeELEELEAELAELQEELEELLEQLSLATEEElQDLAEELEELQQRLAELEEELEEA 218

RING finger, HC subclass, found in mind bomb MIB1, MIB2, 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 first RING-HC finger of MIB1 and MIB2, as well as the second RING-HC finger of MIB1.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCK 309
Cdd:cd16519    1 EECRVCSDKKALVLFQPCGHVVACEECSLRMKKCLQCK 38

RING finger, HC subclass, found in Arabidopsis thaliana MND1-interacting protein 1 (MIP1) and similar proteins; This subfamily includes Arabidopsis thaliana MIP1, RING finger protein 4 (RF4) and RING finger protein 298 (RF298). MIP1 interacts with MND1, HOP2 and XRI1. RF4 and RF298 are putative E3 ubiquitin-protein ligase that may mediate E2-dependent protein ubiquitination. Members of this subfamily contain a typical C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 672067044 270 RAKQCVACQERAHGTVLRPCQHRVLCEPCA-----ASTPECPYCKG 310
Cdd:cd23128    2 RERECVMCMEEERSVVFLPCAHQVVCSGCNdlhekKGMRECPSCRG 47

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 672067044  152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADS---DRQLALQRKEEVEAQV-KQLQEELEGL 226
Cdd:COG4913   700 ELEELEEELDELKGEIGRLEKELEQAEEELDELQDRLEAAEDLARLELRallEERFAAALGDAVERELrENLEERIDAL 778

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044 152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADSD-------RQLALQRKEEVEAQVKQLQEELE 224
Cdd:COG4372   67 ELEQARSELEQLEEELEELNEQLQAAQAELAQAQEELESLQEEAEELQEEleelqkeRQDLEQQRKQLEAQIAELQSEIA 146

second 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 second RING-HC finger.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCK 309
Cdd:cd16725    1 EECVVCSDKKASVLFKPCGHMCACEGCAALMKKCVQCR 38

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044  152 ELARVRRQLDEAKRKIRQWEESWQQVKQAC-----------DAWQREAQEAKERARVADSDRQL-------ALQRKEEVE 213
Cdd:COG4913   339 RLEQLEREIERLERELEERERRRARLEALLaalglplpasaEEFAALRAEAAALLEALEEELEAleealaeAEAALRDLR 418

                          90
                  ....*....|...
gi 672067044  214 AQVKQLQEELEGL 226
Cdd:COG4913   419 RELRELEAEIASL 431

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs 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), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYCKG 310
Cdd:cd16713    8 RTCKVCMDKEVSIVFIPCGHLVVCTECAPSLRKCPICRA 46

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
                 ....*....|....*....|....*....|....*....|..
gi 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCA-----ASTPECPYC 308
Cdd:cd16518    1 RDCVVCFESEVVAALVPCGHNLFCMECAnriceKSDPECPVC 42

HC subclass of RING (RING-HC) finger and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers. Some have a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle, and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 672067044 274 CVACQERAHGTVLRPCQHrVLCEPCA-----ASTPECPYC 308
Cdd:cd16449    3 CPICLERLKDPVLLPCGH-VFCRECIrrlleSGSIKCPIC 41

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 672067044 152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERARVADSDRQLALQRKEEVEAQVKQLQEELEGLG 227
Cdd:COG4372   95 ELAQAQEELESLQEEAEELQEELEELQKERQDLEQQRKQLEAQIAELQSEIAEREEELKELEEQLESLQEELAALE 170

first RING finger, HC subclass, found in mind bomb 2 (MIB2) and similar proteins; MIB2, also known as novel zinc finger protein (Novelzin), putative NF-kappa-B-activating protein 002N, skeletrophin, or zinc finger ZZ type with ankyrin repeat domain protein 1, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands. It promotes Delta ubiquitylation and endocytosis in Notch activation. Overexpression of MIB2 activates NF-kappaB and interferon-stimulated response element (ISRE) reporter activity. Moreover, MIB2 acts as a novel component of the activated B-cell CLL/lymphoma 10 (BCL10) complex and controls BCL10-dependent NF-kappaB activation. It also functions as a founder myoblast-specific protein that regulates myoblast fusion and muscle stability. MIB2 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 two C3HC4-type RING-HC fingers. This model corresponds to the first RING-HC finger.

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 672067044 273 QCVACQERAHGTVLRPCQHRVLCEPCAASTPECPYC 308
Cdd:cd16726    2 ECLVCSELAALVRFEPCQHSIVCEECARRMKKCIKC 37

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 672067044   152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDawQREAQEAKERARVadsdrQLALQRKEEVEAQVKQLQEELEGLG 227
Cdd:TIGR02168  359 ELEELEAELEELESRLEELEEQLETLRSKVA--QLELQIASLNNEI-----ERLEARLERLEDRRERLQQEIEELL 427

RING finger, HC subclass, found in Casitas B-lineage lymphoma (Cbl) proteins; The Cbl adaptor protein family contains a small class of RING-type E3 ubiquitin ligases with oncogenic activity, which is represented by three mammalian members, c-Cbl, Cbl-b and Cbl-c, as well as two invertebrate Cbl-family proteins, D-Cbl in Drosophila and Sli-1 in C. elegans. Cbl proteins function as potent negative regulators of various signaling cascades in a wide range of cell types. They play roles in ubiquitinating activated tyrosine kinases and targeting them for degradation. D-Cbl associates with the Drosophila epidermal growth factor receptor (EGFR) and overexpression of D-Cbl in the eye of Drosophila embryos inhibits EGFR-dependent photoreceptor cell development. Sli-1 is a negative regulator of the Let-23 receptor tyrosine kinase, an EGFR homolog, in vulva development. Cbl proteins in this subfamily consist of a highly conserved N-terminal half that includes 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) and a C3HC4-type RING-HC finger, both of which are required for Cbl-mediated downregulation of RTKs, and a divergent C-terminal region.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 672067044 267 FQLrakqCVACQERAHGTVLRPCQHrVLCEPCAAS-----TPECPYCK 309
Cdd:cd16502    1 FQL----CKICAENDKDVRIEPCGH-LLCTPCLTSwqdsdGQTCPFCR 43

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 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCAAS----TPECPYCK 309
Cdd:cd16789    1 SECVICLSDPRDTAVLPCRHLCLCSDCAEVlryqSNKCPICR 42

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044   152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKERAR-------VADSDRQLALQRKEEVEAQVKQLQEELE 224
Cdd:TIGR02168  268 KLEELRLEVSELEEEIEELQKELYALANEISRLEQQKQILRERLAnlerqleELEAQLEELESKLDELAEELAELEEKLE 347

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 672067044   225 GLgLSSLPGLRSLGDISDIPLPKLHSLQSQLRLDLEAVDGVIFQLRAKQ 273
Cdd:TIGR02168  348 EL-KEELESLEAELEELEAELEELESRLEELEEQLETLRSKVAQLELQI 395

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 672067044 272 KQCVACQERAHGTVLRPCQHRVLCEPCA----ASTPECPYCKGQ 311
Cdd:cd16552    2 EECAICFHHTANTRLVPCGHSHFCGSCAwhifRDTARCPVCRWQ 45

Paraflagellar rod protein; This family consists of several eukaryotic paraflagellar rod component proteins. The eukaryotic flagellum represents one of the most complex macromolecular structures found in any organizm and contains more than 250 proteins. In addition to its locomotive role, the flagellum is probably involved in nutrient uptake since receptors for host low-density lipoproteins are localized on the flagellar membrane as well as on the flagellar pocket membrane.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 672067044  158 RQLDEAKRKIRQWEESWQQVKQACDAWQREAQEaKERARvadsdRQLALQRKEEVEAQVKQLQEE 222
Cdd:pfam05149  37 KQRKRFKTQRRESDKFLQQNVEQQQKLWREIEE-LEREL-----QKLAEERREEVEDRIEAVERE 95

RING finger, HC subclass, found in RNA-binding protein MEX3D; MEX3D, also known as RING finger and KH domain-containing protein 1 (RKHD1), RING finger protein 193 (RNF193), or TINO, is an RNA-binding phosphoprotein that controls the stability of the transcripts coding for the anti-apoptotic protein BCL-2, and negatively regulates BCL-2 in HeLa cells. MEX3D 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, MEX3D shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 672067044 271 AKQCVACQERAHGTVLRPCQHRVLCEPCA-----ASTPECPYC 308
Cdd:cd16723   10 ARECVVCFESEVIAALVPCGHNLFCMECAiricgKSEPECPAC 52

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044  152 ELARVRRQLDEAKRKIRQW--EESWQQVKQACDAWQREAQEAKERARVADSDRQLALQRKEEVEAQ--------VKQLQE 221
Cdd:COG4913   266 AARERLAELEYLRAALRLWfaQRRLELLEAELEELRAELARLEAELERLEARLDALREELDELEAQirgnggdrLEQLER 345

                  ....*
gi 672067044  222 ELEGL 226
Cdd:COG4913   346 EIERL 350

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
                 ....*....|....*....|....*....|....*....|..
gi 672067044 273 QCVACQERAHGTVLRPCQHRVLCEPCA-----ASTPECPYCK 309
Cdd:cd16785    6 ECTICYENAVDTVIYTCGHMCLCYACGlrlkkMLNACCPICR 47

Domain of unknown function (DUF4200); This family is found in eukaryotes. It is a coiled-coil domain of unknwon function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044  152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEAKER----ARVADSDRQLALQR-------KEEVEAQVKQLQ 220
Cdd:pfam13863   7 EMFLVQLALDAKREEIERLEELLKQREEELEKKEQELKEDLIKfdkfLKENDAKRRRALKKaeeetklKKEKEKEIKKLT 86

                  ....*.
gi 672067044  221 EELEGL 226
Cdd:pfam13863  87 AQIEEL 92

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672067044 152 ELARVRRQLDEAKRKIRQWEESWQQVKQACDAWQREAQEA-KERARVADSDRQLALQRKE------EVEAQVKQLQEELE 224
Cdd:COG4372   81 ELEELNEQLQAAQAELAQAQEELESLQEEAEELQEELEELqKERQDLEQQRKQLEAQIAElqseiaEREEELKELEEQLE 160

                 ..
gi 672067044 225 GL 226
Cdd:COG4372  161 SL 162