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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663 117 CSICLLCLST-SPIHVTQCDHFMHATCFCRYLQECSD---GFQKEIQDAQPHMKEKVVTNILCPVCREQL 182
Cdd:cd16470    5 CVICLYGFQEgDAFTKTPCYHYFHSHCLARYIQHMEEnlkEEQEEQEERPRAQTEQEQFQVLCPVCREPL 74

RWD domain of RING finger protein 25 (RNF25) and related proteins; RNF25 (EC 2.3.2.27), also known as AO7, is a putative E3 ubiquitin-protein ligase that was initially identified as an interacting protein of the E2 ubiquitin-conjugating enzyme, Ubc5B. It is ubiquitously expressed in various tissues and is predominantly localized in the nucleus. RNF25 activates nuclear factor (NF)-kappaB-dependent gene expression upon stimulation with interleukin-1 beta (IL-1beta), or tumor necrosis factor (TNF), or overexpression of NF-kappaB-inducing kinase. It interacts with the p65 transactivation domain (TAD) and modulates its transcriptional activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663   1 MEAEIEALCSIW-DGVHVAeaSGNNEERHLKHKIKSLEDEMMSA---SVVIEMTIFSGYPSVPPRVVLSNPRGIGEPEFQ 76
Cdd:cd23818    1 LEEELEALEAIYpDELKVV--SEDGAPTELSITLHPATADDESEqyvRLTLVITLPPGYPEEPPKISLRNPRGLSDARLA 78

                         90       100       110
                 ....*....|....*....|....*....|..
gi 268570663  77 ELQRQIRRIVEENSdEMPIICEIFQHCCDYLA 108
Cdd:cd23818   79 RLLSLLKELAEERA-GEPMLFELIELAKEFLT 109

RING finger, H2 subclass, found in RING finger protein 25 (RNF25) and similar proteins; RNF25, also known as AO7, is a putative E3 ubiquitin-protein ligase that was initially identified as an interacting protein of the E2 ubiquitin-conjugating enzyme, Ubc5B. It is ubiquitously expressed in various tissues and predominantly localized in the nucleus. RNF25 activates the nuclear factor (NF)-kappaB-dependent gene expression upon stimulation with Interleukin-1 beta (IL-1beta), or tumor necrosis factor (TNF), or overexpression of NF-kappaB-inducing kinase. It interacts with the p65 transactivation domain (TAD) and modulates its transcriptional activity. RNF25 contains an N-terminal RWD domain, a C3H2C3-type RING-H2 finger, and a C-terminal Pro-rich region. Both the RING-H2 finger and the C-terminal regions of RNF25 are necessary for transcriptional activation.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663 117 CSICLLCLST-SPIHVTQCDHFMHATCFCRYLQECSD---GFQKEIQDAQPHMKEKVVTNILCPVCREQL 182
Cdd:cd16470    5 CVICLYGFQEgDAFTKTPCYHYFHSHCLARYIQHMEEnlkEEQEEQEERPRAQTEQEQFQVLCPVCREPL 74

RWD domain of RING finger protein 25 (RNF25) and related proteins; RNF25 (EC 2.3.2.27), also known as AO7, is a putative E3 ubiquitin-protein ligase that was initially identified as an interacting protein of the E2 ubiquitin-conjugating enzyme, Ubc5B. It is ubiquitously expressed in various tissues and is predominantly localized in the nucleus. RNF25 activates nuclear factor (NF)-kappaB-dependent gene expression upon stimulation with interleukin-1 beta (IL-1beta), or tumor necrosis factor (TNF), or overexpression of NF-kappaB-inducing kinase. It interacts with the p65 transactivation domain (TAD) and modulates its transcriptional activity.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663   1 MEAEIEALCSIW-DGVHVAeaSGNNEERHLKHKIKSLEDEMMSA---SVVIEMTIFSGYPSVPPRVVLSNPRGIGEPEFQ 76
Cdd:cd23818    1 LEEELEALEAIYpDELKVV--SEDGAPTELSITLHPATADDESEqyvRLTLVITLPPGYPEEPPKISLRNPRGLSDARLA 78

                         90       100       110
                 ....*....|....*....|....*....|..
gi 268570663  77 ELQRQIRRIVEENSdEMPIICEIFQHCCDYLA 108
Cdd:cd23818   79 RLLSLLKELAEERA-GEPMLFELIELAKEFLT 109

RWD domain; This domain was identified in WD40 repeat proteins and Ring finger domain proteins. The function of this domain is unknown. GCN2 is the alpha-subunit of the only translation initiation factor (eIF2 alpha) kinase that appears in all eukaryotes. Its function requires an interaction with GCN1 via the domain at its N-terminus, which is termed the RWD domain after three major RWD-containing proteins: RING finger-containing proteins, WD-repeat-containing proteins, and yeast DEAD (DEXD)-like helicases. The structure forms an alpha + beta sandwich fold consisting of two layers: a four-stranded antiparallel beta-sheet, and three side-by-side alpha-helices.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663    2 EAEIEALCSIWDGVHVAEASGNNEERHLKHKIKSLEDEMMSA---SVVIEMTIFSGYPSVPPRVVLSNPRGIGEPEFQEL 78
Cdd:pfam05773   4 EEELEALESIYPDEFEVISDSPYESLEIEIKLSLDSDESDSShlpPLVLKFTLPEDYPDEPPKISLSSPWNLSDEQVLSL 83

                          90       100
                  ....*....|....*....|....*....
gi 268570663   79 QRQIRRIVEENSdEMPIICEIFQHCCDYL 107
Cdd:pfam05773  84 LEELEELAEENL-GEVMIFELIEWLQENL 111

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-1 (UBR1), E3-alpha-2 (UBR2), and similar proteins; Two UBR family members, UBR1 and UBR2, are major N-recognin ubiquitin ligases that both function in the N-end rule degradation pathway. They can recognize substrate proteins with type-1 (basic) and type-2 (bulky hydrophobic) N-terminal residues as part of N-degrons and an internal lysine residue for ubiquitin conjugation. They also function in a quality control pathway for degradation of unfolded cytosolic proteins. Their action is stimulated by Hsp70. Moreover, UBR1 and UBR2 are negative regulators of the leucine-mTOR signaling pathway. Leucine might activate this pathway in part through inhibition of their ubiquitin ligase activity. In yeast, only one E3, encoded by UBR1, mediates the recognition of substrates by the N-end rule pathway. Saccharomyces cerevisiae UBR1 also functions as an additional E3 ligase in the endoplasmic reticulum-associated protein degradation (ERAD). It can provide ubiquitin ligation activity for the ERAD substrate mutated Ste6 (sterile). Schizosaccharomyces pombe UBR1 is a critical regulator that influences the oxidative stress response via degradation of active Pap1 basic leucine zipper (bZIP) transcription factor in the nucleus. Both UBR1 and UBR2 contain an N-terminal ubiquitin-recognin (UBR) box involved in binding type-1 (basic) N-end rule substrate, an N-domain (also known as ClpS domain) required for type-2 (bulky hydrophobic) N-end rule substrate recognition, a C3H2C3-type RING-H2 finger, and a C-terminal UBR-specific autoinhibitory (UAIN) domain.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 268570663 120 CLLCLSTspIHVTQCDHFMHATCFCRYLQECSDGFQKEIQDAQPHMKEKVVTNILCPVCReqlTDANTI 188
Cdd:cd16482    2 CILCQEG--LHISSCGHVMHYDCWQRYFDSVRLREQRRPAFRRHHSEDVSKGEFLCPLCK---SLSNTV 65

RWD, DRWD, and ELF domain family; The family includes the RWD, double-RWD (DRWD), and ELF domains. They belong to the ubiquitin-conjugating (UBC) superfamily that represents a structural domain with an alpha-beta(4)-alpha(3) core fold. The RWD domain (named after three major RWD-containing proteins: RING finger, WD-repeat-containing proteins and DEXD-like helicases) mediates protein-protein interactions in a variety of pathways in eukaryotes. The DRWD domain is responsible for substrate binding. It is involved in interactions with other kinetochore proteins. The ELF (N-terminal E2-like fold) domain is found in all Fanconi anemia group L protein (FANCL) homologs. It is required to promote efficient DNA damage-induced FANCD2 (Fanconi anemia group D2 protein) monoubiquitination in vertebrate cells.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 268570663   7 ALCSIW-DGVHVAEasgNNEERHLKHKIkSLEDEMMSASVVIEMTIFSGY-PSVPPRVVLSNPRGIGEPEFQELQRQIRR 84
Cdd:cd11605    1 ALESIYgDELEVLS---DDSPLRFSIRL-SPEEEEDDPPLELEFTLPPGYpPEEPPLITLRSPKLSSAERLSLLKLELEE 76

                         90
                 ....*....|....*....
gi 268570663  85 IVEENsDEMPIICEIFQHC 103
Cdd:cd11605   77 AAEEN-LGEPMLFDLVEAL 94

zinc-RING finger domain;

                          10        20        30
                  ....*....|....*....|....*....|....
gi 268570663  117 CSICLLCL-STSPIHVTQCDHFMHATCFCRYLQE 149
Cdd:pfam14634   2 CNKCFKELsKTRPFYLTSCGHIFCEECLTRLLQE 35