WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 451 RILAYCDGLSCLVASQPSpqasflpgfGVKMLSTANMKSSQYIPMHNKQIRGLSFSsQSKGLLLSASLDCTIKLTSLETN 530
Cdd:cd00200  56 DVAASADGTYLASGSSDK---------TIRLWDLETGECVRTLTGHTSYVSSVAFS-PDGRILSSSSRDKTIKVWDVETG 125

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 31542200 531 TVVQTYNT-GRPVWSCCWCLDeNNYVYAGLASGSILIYDLRN 571
Cdd:cd00200 126 KCLTTLRGhTDWVNSVAFSPD-GTFVASSSQDGTIKLWDLRT 166

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 31542200   287 TCTICLEQWTNagDHRISALRCGHLFGFRCISKWLKgQTRKCPQCN 332
Cdd:pfam13639   2 ECPICLEEFEE--GDKVVVLPCGHHFHRECLDKWLR-SSNTCPLCR 44

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 31542200    288 CTICLEQWTnagdHRISALRCGHLFGFRCISKWLKGQTRKCPQC 331
Cdd:smart00184   1 CPICLEEYL----KDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

WD40 repeat [General function prediction only];

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31542200 496 HNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYNT-GRPVWSCCWCLDeNNYVYAGLASGSILIYDLR 570
Cdd:COG2319 203 HTGAVRSVAFSPDGK-LLASGSADGTVRLWDLATGKLLRTLTGhSGSVRSVAFSPD-GRLLASGSADGTVRLWDLA 276

N1R/p28-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 31542200  274 PNMLSAME----DEEGETCTICLEqwtNAGDHRISAL------RCGHLFGFRCISKWLKgQTRKCPQCNKK 334
Cdd:PHA02929 159 PSVLSEYEklynRSKDKECAICME---KVYDKEIKNMyfgilsNCNHVFCIECIDIWKK-EKNTCPVCRTP 225

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 31542200 288 CTICLEQWTNAgdHRISALRCGHLFGFRCISKWLKGQTRKCPQC 331
Cdd:cd00162   1 CPICREEMNDR--RPVVLLSCGHTFSRSAIARWLEGSKQKCPFC 42

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 31542200   287 TCTICLEQWTNagDHRISALRCGHLFGFRCISKWLKgQTRKCPQCN 332
Cdd:pfam13639   2 ECPICLEEFEE--GDKVVVLPCGHHFHRECLDKWLR-SSNTCPLCR 44

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 451 RILAYCDGLSCLVASQPSpqasflpgfGVKMLSTANMKSSQYIPMHNKQIRGLSFSsQSKGLLLSASLDCTIKLTSLETN 530
Cdd:cd00200  56 DVAASADGTYLASGSSDK---------TIRLWDLETGECVRTLTGHTSYVSSVAFS-PDGRILSSSSRDKTIKVWDVETG 125

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 31542200 531 TVVQTYNT-GRPVWSCCWCLDeNNYVYAGLASGSILIYDLRN 571
Cdd:cd00200 126 KCLTTLRGhTDWVNSVAFSPD-GTFVASSSQDGTIKLWDLRT 166

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 479 VKMLSTANMKSSQYIPMHNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYNT-GRPVWSCCWCLDeNNYVYA 557
Cdd:cd00200 159 IKLWDLRTGKCVATLTGHTGEVNSVAFSPDGE-KLLSSSSDGTIKLWDLSTGKCLGTLRGhENGVNSVAFSPD-GYLLAS 236

                        90
                ....*....|....
gi 31542200 558 GLASGSILIYDLRN 571
Cdd:cd00200 237 GSEDGTIRVWDLRT 250

RING finger, H2 subclass, found in Arabidopsis thaliana RING-H2 finger A1a (RHA1A), A1b (RHA1B) and similar proteins; This subfamily includes Arabidopsis thaliana RHA1A, RHA1B and XERICO. RHA1A is a probable E3 ubiquitin-protein ligase that may possess E3 ubiquitin ligase activity in vitro. RHA1B possesses E3 ubiquitin-protein ligase activity when associated with the E2 enzyme UBC8 in vitro. XERICO functions on abscisic acid homeostasis at post-translational level, probably through ubiquitin/proteasome-dependent substrate-specific degradation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 31542200 288 CTICLEQWtNAGDHRISALRCGHLFGFRCISKWLKGQTRKCPQC 331
Cdd:cd23121   4 CAICLSDF-NSDEKLRQLPKCGHIFHHHCLDRWIRYNKITCPLC 46

RING finger, H2 subclass, found in the PA-TM-RING ubiquitin ligase family; The PA-TM-RING family represents a group of transmembrane-type E3 ubiquitin ligases, which has been characterized by an N-terminal transient signal peptide, a PA (protease-associated) domain, a TM (transmembrane) domain, as well as a C-terminal C3H2C3-type RING-H2 finger domain. It includes RNF13, RNF167, ZNRF4 (zinc and RING finger 4), GRAIL (gene related to anergy in lymphocytes)/RNF128, RNF130, RNF133, RNF148, RNF149 and RNF150 (which are more closely related), as well as RNF43 and ZNRF3, which have substantially longer C-terminal tail extensions compared with the others. PA-TM-RING proteins are expressed at low levels in all mammalian tissues and species, but they are not present in yeast. They play a common regulatory role in intracellular trafficking/sorting, suggesting that abrogation of their function may result in dysregulation of cellular signaling events in cancer.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 31542200 287 TCTICLEQWTNAGDhrISALRCGHLFGFRCISKWLKgQTRKCPQC 331
Cdd:cd16454   1 TCAICLEEFKEGEK--VRVLPCNHLFHKDCIDPWLE-QHNTCPLC 42

RING finger, H2 subclass, found in RING finger proteins RNF24, RNF122, and similar proteins; This subfamily includes RNF24, RNF122, and similar proteins. RNF24 is an intrinsic membrane protein localized in the Golgi apparatus. It specifically interacts with the ankyrin-repeats domains (ARDs) of TRPC1, -3, -4, -5, -6, and -7, and affects TRPC intracellular trafficking without affecting their activity. RNF122 is a RING finger protein associated with HEK 293T cell viability. It is localized to the endoplasmic reticulum (ER) and the Golgi apparatus, and overexpressed in anaplastic thyroid cancer cells. RNF122 functions as an E3 ubiquitin ligase that can ubiquitinate itself and undergo degradation through its RING finger in a proteasome-dependent manner. Both RNF24 and RNF122 contain an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 31542200 286 ETCTICLEQWTNagDHRISALRCGHLFGFRCISKWLKgQTRKCPQCNKKA 335
Cdd:cd16469   1 DTCAVCLEEFKL--KEELGVCPCGHAFHTKCLKKWLE-VRNSCPICKSPV 47

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 31542200 287 TCTICLEQWTNAgdhriSALRCGHLFGFRCISKWLKGQTRKCPQCNKKAKHSDI 340
Cdd:cd16499   8 KCSVCNDRFKDV-----IITKCGHVFCNECVQKRLETRQRKCPGCGKAFGANDV 56

RING finger, HC subclass, found in Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) and similar proteins; AtRMAs, including AtRma1, AtRma2, and AtRma3, are endoplasmic reticulum (ER)-localized Arabidopsis homologs of human outer membrane of the ER-anchor E3 ubiquitin-protein ligase, RING finger protein 5 (RNF5). AtRMAs possess E3 ubiquitin ligase activity, and may play a role in the growth and development of Arabidopsis. The AtRMA1 and AtRMA3 genes are predominantly expressed in major tissues, such as cotyledons, leaves, shoot-root junction, roots, and anthers, while AtRMA2 expression is restricted to the root tips and leaf hydathodes. AtRma1 probably functions with the Ubc4/5 subfamily of E2. AtRma2 is likely involved in the cellular regulation of ABP1 expression levels through interacting with auxin binding protein 1 (ABP1). AtRMA proteins contain an N-terminal C3HC4-type RING-HC finger and a trans-membrane-anchoring domain in their extreme C-terminal region.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 31542200 288 CTICLEQwtnAGDHRISalRCGHLFGFRCISKWLKGQ--TRKCPQC 331
Cdd:cd16745   3 CNICLDL---AQDPVVT--LCGHLFCWPCLHKWLRRQssQPECPVC 43

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 496 HNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYnTG--RPVWSCCWcLDENNYVYAGLASGSILIYDLRnTN 573
Cdd:cd00200  50 HTGPVRDVAASADGT-YLASGSSDKTIRLWDLETGECVRTL-TGhtSYVSSVAF-SPDGRILSSSSRDKTIKVWDVE-TG 125

                ....*.
gi 31542200 574 TYIQEL 579
Cdd:cd00200 126 KCLTTL 131

RING finger, H2 subclass, found in 43 kDa receptor-associated protein of the synapse (Rapsyn) and similar proteins; Rapsyn, also known as acetylcholine receptor (AChR)-associated 43 kDa protein or RING finger protein 205 (RNF205), is a 43 kDa postsynaptic protein that plays an essential role in the clustering and maintenance of AChR in the postsynaptic membrane of the motor endplate. AChRs enable the transport of rapsyn from the Golgi complex to the plasma membrane through a molecule-specific interaction. Rapsyn also mediates subsynaptic anchoring of protein kinase A (PKA) type I in close proximity to the postsynaptic membrane, which is essential for synapse maintenance. Its mutations in humans cause endplate AChR deficiency and myasthenic syndrome. Rapsyn contains an N-terminal myristoylation signal required for membrane association, seven tetratricopeptide repeats (TPRs) that subserve rapsyn self-association, a coiled-coil domain responsible for the binding of determinants within the long cytoplasmic loop of each AChR subunit, a C3H2C3-type RING-H2 finger that binds to the cytoplasmic domain of beta-dystroglycan and to S-NRAP and links rapsyn to the subsynaptic cytoskeleton, and a serine phosphorylation site.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 31542200 288 CTICLEQWTNAgDHRISALRCGHLFGFRCISKWLKGQTRKCPQCNK 333
Cdd:cd16478   4 CGMCGESIGEK-NEQLQALPCSHIFHLKCLQTNLRGGTRGCPNCRR 48

RING finger, H2 subclass, found in Arabidopsis thaliana protein WAV3 homolog 2 (WAVH2) and similar proteins; WAVH2, also known as RING-type E3 ubiquitin transferase WAVH2, is a probable E3 ubiquitin-protein ligase involved in the regulation of root growth. It acts as a positive regulator of root gravitropism. WAVH2 contains a C3H2C3-type RING-H2 finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 31542200 286 ETCTICLEQWTNAGDHRISALRCGHLFGFRCISKWLKGQTRKCPQCNKKAKH 337
Cdd:cd23114   5 SECSICLETMKPGSGHAIFTAECSHSFHFECIAGNVRHGNLRCPVCRAKWKE 56

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 31542200 286 ETCTICLEQwtnagDHRISALRCGHLFGFRCISKWLKGQTRKCPQC 331
Cdd:cd16449   1 LECPICLER-----LKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

RING finger, H2 subclass, found in RING finger protein 165 (RNF165) and similar proteins; RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. RNF165 contains two serine rich domains, a nuclear localization signal, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is responsible for the enhancement of BMP-Smad1/5/8 signaling in the spinal cord.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 31542200 281 EDEEGETCTICLEQWTNAGDHRisALRCGHLFGFRCISKWLkGQTRKCPQC 331
Cdd:cd16682   3 ESDTDEKCTICLSMLEDGEDVR--RLPCMHLFHQLCVDQWL-AMSKKCPIC 50

WD40 repeat [General function prediction only];

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31542200 496 HNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYNT-GRPVWSCCWCLDeNNYVYAGLASGSILIYDLR 570
Cdd:COG2319 203 HTGAVRSVAFSPDGK-LLASGSADGTVRLWDLATGKLLRTLTGhSGSVRSVAFSPD-GRLLASGSADGTVRLWDLA 276

RING finger, H2 subclass, found in RING finger proteins RNF111, RNF165, and similar proteins; The family includes RING finger proteins RNF111, RNF165, and similar proteins. RNF111, also known as Arkadia, is a nuclear E3 ubiquitin-protein ligase that targets intracellular effectors and modulators of transforming growth factor beta (TGF-beta)/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. It also interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signaling pathways. The N-terminal half of RNF111 harbors three SUMO-interacting motifs (SIMs). It thus functions as a SUMO-targeted ubiquitin ligase (STUbL) that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response, as well as triggers degradation of signal-induced polysumoylated proteins, such as the promyelocytic leukemia protein (PML). RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. Both RNF165 and RNF111 contain a C-terminal C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 31542200 286 ETCTICLEQWTNAGDHRisALRCGHLFGFRCISKWLKGQtRKCPQC 331
Cdd:cd16474   1 EKCTICLSDFEEGEDVR--RLPCMHLFHQECVDQWLSTN-KRCPIC 43

RING finger, H2 subclass, found in RING finger protein 122 (RNF122) and similar proteins; RNF122 is a RING finger protein associated with HEK 293T cell viability. It is localized to the endoplasmic reticulum (ER) and the Golgi apparatus, and overexpressed in anaplastic thyroid cancer cells. RNF122 functions as an E3 ubiquitin ligase that can ubiquitinate itself and undergo degradation through its RING finger in a proteasome-dependent manner. It interacts with calcium-modulating cyclophilin ligand (CAML), which is not a substrate, but a stabilizer of RNF122. RNF122 contains an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 31542200 286 ETCTICLEQWTnaGDHRISALRCGHLFGFRCISKWLKGQTrKCPQCNK 333
Cdd:cd16676   1 QTCAVCLEDFK--TKDELGVLPCQHAFHRKCLVKWLEIRC-VCPMCNK 45

RING finger, HC subclass, found in RING finger protein RNF5, RNF185 and similar proteins; RNF5 and RNF185 are E3 ubiquitin-protein ligases that are anchored to the outer membrane of the endoplasmic reticulum (ER). RNF5 acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis, and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. RNF185 controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical endoplasmic reticulum-associated degradation (ERAD) model substrates. Moreover, both RNF5 and RNF185 play important roles in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) are also included in this family. They possess E3 ubiquitin-protein ligase activity and may play a role in the growth and development of Arabidopsis. All members of this family contain a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 31542200 288 CTICLEQWTNAgdhriSALRCGHLFGFRCISKWL--KGQTRKCPQCN 332
Cdd:cd16534   3 CNICLDTASDP-----VVTMCGHLFCWPCLYQWLetRPDRQTCPVCK 44

RING finger, H2 subclass, found in RING finger protein 103 (RNF103) and similar proteins; RNF103, also known as KF-1 or zinc finger protein 103 homolog (Zfp-103), is an endoplasmic reticulum (ER)-resident E3 ubiquitin-protein ligase that is widely expressed in many different organs, including brain, heart, kidney, spleen, and lung. It is involved in the ER-associated degradation (ERAD) pathway by interacting with components of the ERAD pathway, including Derlin-1 and VCP. RNF103 contains several hydrophobic regions at its N-terminal and middle regions, as well as a C-terminal C3H2C3-type RING-H2 finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 31542200 284 EGETCTICLEQWTNAGDHRIsaLRCGHLFGFRCISKWLKGQTRKCPQCNKKAK 336
Cdd:cd16473   3 ECEECAICLENYQNGDLLRG--LPCGHVFHQNCIDVWLERDNHCCPVCRWPVY 53

RING-type zinc-finger; This zinc-finger is a typical RING-type of plant ubiquitin ligases.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 31542200   288 CTICLEQWTNAgdhrisALRCGHLFGFRCI--SKWLKGQTRKCP 329
Cdd:pfam13445   1 CPICLELFTDP------VLPCGHTFCRECLeeMSQKKGGKFKCP 38

RING finger, H2 subclass, found in RING finger protein 111 (RNF111) and similar proteins; RNF111, also known as Arkadia, is a nuclear E3 ubiquitin-protein ligase that targets intracellular effectors and modulators of transforming growth factor beta (TGF-beta)/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. It acts as an amplifier of Nodal signals, and enhances the dorsalizing activity of limiting amounts of Xnr1, a Nodal homolog, and requires Nodal signaling for its function. The loss of RNF111 results in early embryonic lethality, with defects attributed to compromised Nodal signaling. RNF111 also regulates tumor metastasis by modulation of the TGF-beta pathway. Its ubiquitination can be modulated by the four and a half LIM-only protein 2 (FHL2) that activates TGF-beta signal transduction. Furthermore, RNF111 interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signaling pathways. In addition, RNF111 has been identified as a small ubiquitin-like modifier (SUMO)-binding protein with clustered SUMO-interacting motifs (SIMs) that together form a SUMO-binding domain (SBD). It thus functions as a SUMO-targeted ubiquitin ligase (STUbL) that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response, as well as triggers degradation of signal-induced polysumoylated proteins, such as the promyelocytic leukemia protein (PML). The N-terminal half of RNF111 harbors three SIMs. Its C-terminal half show high sequence similarity with RING finger protein 165 (RNF165), where it contains two serine rich domains, two nuclear localization signals, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is required for polyubiqutination and proteasome-dependent degradation of phosphorylated forms of Smad2/3 and three major negative regulators of TGF-beta signaling, Smad7, SnoN and c-Ski.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 31542200 279 AMEDEEGETCTICLEQWTNAGDHRisALRCGHLFGFRCISKWLKgQTRKCPQC 331
Cdd:cd16681   4 GTEEDTEEKCTICLSILEEGEDVR--RLPCMHLFHQVCVDQWLI-TNKKCPIC 53

RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins; This subfamily includes RING finger proteins RNF38, RNF44, and similar proteins. RNF38 is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 is an uncharacterized RING finger protein that shows high sequence similarity to RNF38. Both RNF38 and RNF44 contain a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C3-type RING-H2 finger. In addition, RNF38 harbors two potential nuclear localization signals.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 31542200 284 EGETCTICLEQWTNagDHRISALRCGHLFGFRCISKWLKGQtRKCPQC 331
Cdd:cd16472   1 DQTQCVVCMCDYEK--RQLLRVLPCSHEFHAKCIDKWLKTN-RTCPIC 45

RING finger, H2 subclass, found in rice E3 ubiquitin-protein ligase EL5 and similar proteins; EL5, also known as protein ELICITOR 5, is an E3 ubiquitin-protein ligase containing an N-terminal transmembrane domain and a C3H2C3-type RING-H2 finger that is a binding site for ubiquitin-conjugating enzyme (E2). It can be rapidly induced by N-acetylchitooligosaccharide elicitor. EL5 catalyzes polyubiquitination via the Lys48 residue of ubiquitin, and thus plays a crucial role as a membrane-anchored E3 in the maintenance of cell viability after the initiation of root primordial formation in rice. It also acts as an anti-cell death enzyme that might be responsible for mediating the degradation of cytotoxic proteins produced in root cells after the actions of phytohormones. Moreover, EL5 interacts with UBC5b, a rice ubiquitin carrier protein, through its RING-H2 finger. EL5 is an unstable protein, and its degradation is regulated by the C3H2C3-type RING-H2 finger in a proteasome-independent manner.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 31542200 288 CTICLEQWTNaGDHRISALRCGHLFGFRCISKWLKGQTrKCPQCN 332
Cdd:cd16461   2 CAICLSDYEN-GEELRRLPECKHAFHKECIDEWLKSNS-TCPLCR 44

Modified RING finger, HC subclass (C4C4-type), found in tripartite motif-containing protein 37 (TRIM37) and similar proteins; TRIM37, also known as mulibrey nanism protein, or MUL, is a peroxisomal E3 ubiquitin-protein ligase that is involved in the tumorigenesis of several cancer types, including pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer, and sporadic fibrothecoma. It mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. Moreover, TRIM37 possesses anti-HIV-1 activity, and interferes with viral DNA synthesis. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction, and hepatomegaly. TRIM37 belongs to the C-VIII 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 C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a MATH (meprin and TRAF-C homology) domain positioned C-terminal to the RBCC domain. Its MATH domain has been shown to interact with the TRAF (TNF-Receptor-Associated Factor) domain of six known TRAFs in vitro.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 31542200 287 TCTICLEQWTNAgdhrISALRCGHLFGFRCISKWLKGQTRKCPQC 331
Cdd:cd16619   2 RCFICMEKLRDP----RLCPHCSKLFCKGCIRRWLSEQRSSCPHC 42

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 31542200 284 EGETCTICLEQWtnagdHRISALRCGHLFGFRCISKWLKGQTRkCPQC 331
Cdd:cd16561   1 GEQECSICLEDL-----NDPVKLPCDHVFCEECIRQWLPGQMS-CPLC 42

RING finger, H2 subclass, found in RING finger proteins RNF43, ZNRF3, and similar proteins; RNF43 and ZNRF3 (also known as RNF203) are transmembrane E3 ubiquitin-protein ligases that belong to the PA-TM-RING ubiquitin ligase family, characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region. Both RNF43 and RNF203 function as tumor suppressors involved in the regulation of Wnt/beta-catenin signaling. They negatively regulate Wnt signaling by interacting with complexes of frizzled (FZD) receptors and low-density lipoprotein receptor-related protein (LRP) 5/6, which leads to ubiquitination of FZD and endocytosis of the Wnt receptor. Dishevelled (DVL), a positive Wnt regulator, is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. They also associate with R-spondin 1 (RSPO1). This interaction may block FZD ubiquitination and enhances Wnt signaling.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 31542200 288 CTICLEQWTNAGDHRIsaLRCGHLFGFRCISKWLKgQTRKCPQCN 332
Cdd:cd16666   2 CAICLEEYEEGQELRV--LPCQHEFHRKCVDPWLL-QNHTCPLCL 43

DNA polymerase III subunits gamma and tau; Validated

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200   35 EPATPTEVVSNGAPLQPAPAELANSQGGAHVQPAPAE------VVSSQDGLPTLQPLPPASIDLTEEVQPSEENMEVVNP 108
Cdd:PRK07764 599 GPPAPASSGPPEEAARPAAPAAPAAPAAPAPAGAAAApaeasaAPAPGVAAPEHHPKHVAVPDASDGGDGWPAKAGGAAP 678

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200  109 GTSEEPSQGSGANPTAGAARSVSmnnfisglqrlhnmlellRPPPADHSVGPIRTRRRMAPILRARAGESQRQDNGRYVP 188
Cdd:PRK07764 679 AAPPPAPAPAAPAAPAGAAPAQP------------------APAPAATPPAGQADDPAAQPPQAAQGASAPSPAADDPVP 740

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....
gi 31542200  189 HTPLYAYFQVSRSQPYPLPAAHDSETRNPPSGTDSDSDGSAEDEEVVVQAEEPE 242
Cdd:PRK07764 741 LPPEPDDPPDPAGAPAQPPPPPAPAPAAAPAAAPPPSPPSEEEEMAEDDAPSMD 794

Component of SCF ubiquitin ligase and anaphase-promoting complex [Posttranslational modification, protein turnover, chaperones / Cell division and chromosome partitioning];

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 31542200 286 ETCTICLEQWTNAGDHRISALRCGHLFGFRCISKWLKGQTrKCPQCNKK 334
Cdd:COG5194  32 GTCPECQFGMTPGDECPVVWGVCNHAFHDHCIYRWLDTKG-VCPLDRQT 79

modified RING finger, H2 subclass (C3H2C2D-type), found in RING-box protein 1 (RBX1) and similar proteins; RBX1, also known as Hrt1, protein ZYP, RING finger protein 75 (RNF75), or regulator of cullins 1 (ROC1), is an E3 ubiquitin-protein ligase necessary for ubiquitin ligation activity of multimeric cullin (Cul)-RING E3 ligases (CRLs). RBX1-containing CRLs are involved in the NEDD8 pathway; RBX1 specifically regulates NEDD8ylation of Cul1-4. It can also bind and activate HIV-1 Vif-Cullin5 E3 ligase complex in vitro. Moreover, RBX1 is an essential element of Skp1/Cullin/F-box (SCF) E3-ubiquitin ligase complexes that target diverse proteins for proteasome-mediated degradation. It is a direct functional target of miR-194 and plays an important role in proliferation and migration of gastric cancer (GC) cells. RBX1 is also an essential component of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex that functions as a regulator of NFE2-related factor 2 (NRF2) and plays a key role in NRF2 pathway deregulation in multiple tumor types, including ovarian carcinomas (OVCA) and papillary thyroid carcinoma (PTC). Furthermore, RBX1 associates with DDB1, Cul4A, and Fbxw5 to form the Fbxw5-DDB1-Cul4A-Rbx1 complex that may function as a dual SUMO/ubiquitin ligase suppressing c-Myb activity through sumoylation or ubiquitination. RBX1 contains a C-terminal modified RING-H2 finger that is of C3H2C2D-type, rather than the canonical C3H2C3-type. The modified RING-H2 finger is essential for its ligase activity.

                        10        20
                ....*....|....*....|....*...
gi 31542200 308 CGHLFGFRCISKWLKgqTRK-CPQCNKK 334
Cdd:cd16485  36 CNHAFHFHCISRWLK--TRQvCPLDNRE 61

WD40 repeat [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 459 LSCLVASQPSPQASFLPGFGVKMLSTANMKSSQYIPMHNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYNT 538
Cdd:COG2319  82 LSVAFSPDGRLLASASADGTVRLWDLATGLLLRTLTGHTGAVRSVAFSPDGK-TLASGSADGTVRLWDLATGKLLRTLTG 160

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 31542200 539 -GRPVWSCCWCLDeNNYVYAGLASGSILIYDLRnTNTYIQEL 579
Cdd:COG2319 161 hSGAVTSVAFSPD-GKLLASGSDDGTVRLWDLA-TGKLLRTL 200

Modified RING finger, H2 subclass (C3H2C2D-type), found in zinc finger SWIM domain-containing protein 2 (ZSWIM2) and similar proteins; ZSWIM2, also known as MEKK1-related protein X (MEX) or ZZ-type zinc finger-containing protein 2, is a testis-specific E3 ubiquitin ligase that promotes death receptor-induced apoptosis through Fas, death receptor (DR) 3 and DR4 signaling. ZSWIM2 is self-ubiquitinated and targeted for degradation through the proteasome pathway. It acts as an E3 ubiquitin ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c, or UbcH6. ZSWIM2 contains four putative zinc-binding domains including an N-terminal SWIM (SWI2/SNF2 and MuDR) domain critical for its ubiquitination, and two modified RING-H2 fingers separated by a ZZ zinc finger domain, which was required for interaction with UbcH5a and its self-association. This model corresponds to the second RING-H2 finger, which is not a canonical C3H2C3-type, but a modified C3H2C2D-type.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 31542200 288 CTICLEQWtNAGDHrISALRCGHLFGFRCISKWLKGQTRKCPQCNK 333
Cdd:cd16486   2 CRICLKAF-QLGQH-VRTLPCRHKFHRDCIDNWLLHSRNSCPIDGQ 45

WD40 repeat [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31542200 479 VKMLSTANMKSSQYIPMHNKQIRGLSFSSQSKgLLLSASLDCTIKLTSLETNTVVQTYN-TGRPVWSCCWCLDeNNYVYA 557
Cdd:COG2319 270 VRLWDLATGELLRTLTGHSGGVNSVAFSPDGK-LLASGSDDGTVRLWDLATGKLLRTLTgHTGAVRSVAFSPD-GKTLAS 347

                        90
                ....*....|....
gi 31542200 558 GLASGSILIYDLRN 571
Cdd:COG2319 348 GSDDGTVRLWDLAT 361

RING finger, H2 subclass, found in RING finger protein 215 (RNF215) and similar proteins; This family includes uncharacterized protein RNF215 and similar proteins. Although its biological function remains unclear, RNF215 shares high sequence similarity with PA-TM-RING ubiquitin ligases, which have been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 31542200 286 ETCTICLEQWTNagDHRISALRCGHLFGFRCISKWLKGQtRKCPQC 331
Cdd:cd16670   1 ESCAVCLDQFYK--NQCLRVLPCLHEFHRDCVDPWLLLQ-QTCPLC 43

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

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 31542200 287 TCTICLEQWTNAgdhrISALRCGHLFGFRCISKWLKGQTRKCPQCNK 333
Cdd:cd16544   4 TCPVCQEVLKDP----VELPPCRHIFCKACILLALRSSGARCPLCRG 46

N1R/p28-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 31542200  274 PNMLSAME----DEEGETCTICLEqwtNAGDHRISAL------RCGHLFGFRCISKWLKgQTRKCPQCNKK 334
Cdd:PHA02929 159 PSVLSEYEklynRSKDKECAICME---KVYDKEIKNMyfgilsNCNHVFCIECIDIWKK-EKNTCPVCRTP 225

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