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        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567 1107 TCILCQEEQEVTVGSRAMVLAAFVQRSTVLSKDRTKTIADPEKYDPLFMHPDLSCGTHTGSCGHVMHAHCWQRYFDSVQA 1186
Cdd:cd16686     1 TCILCQEEQEIKVDNKAMVLAAFVQRSTVMSKNRSRVIHDPEKYDPLFMHPDLSCGTHTGSCGHIMHAHCWQRYFDAVQA 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 293651567 1187 KEQRRQQRLRLHTSYDVENGEFLCPLCECLSNTVIP 1222
Cdd:cd16686    81 KEQRRQQRLRVHTSYDVENGEFLCPLCECLSNTVIP 116

ATP-dependent Clp protease adaptor protein ClpS; In the bacterial cytosol, ATP-dependent protein degradation is performed by several different chaperone-protease pairs, including ClpAP. ClpS directly influences the ClpAP machine by binding to the N-terminal domain of the chaperone ClpA. The degradation of ClpAP substrates, both SsrA-tagged proteins and ClpA itself, is specifically inhibited by ClpS. ClpS modifies ClpA substrate specificity, potentially redirecting degradation by ClpAP toward aggregated proteins.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 293651567   222 EKSDTYYCMLFNDEVHTYEQVIYTLQKAVNCTQKEAIGFATTVDRDGRRSVRYGDFQYCDQAKTVIVRNTSRQTKPLKV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARENGFPLRC 79

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-2 (UBR2) and similar proteins; UBR2, also known as N-recognin-2 or E3alpha-II, is an E3 ubiquitin-protein ligase that plays an important role in maintaining genome integrity and in homologous recombination repair. It regulates the level of the transcription factor Rpn4 (also known as Son1 and Ufd5) through ubiquitylation. The ubiquitin-conjugating enzyme Rad6, another binding partner of URB2, and an additional factor Mub1, are required for the ubiquitin-dependent degradation of Rpn4. UBR2 associates with Mub1 to form a Mub1/Ubr2 complex that regulates the conserved Dsn1 kinetochore protein levels, which is a part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability. As the recognition component of a major cellular proteolytic system, UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both spermatocytes and somatic cells. UBR2 also mediates transcriptional silencing during spermatogenesis via histone ubiquitination. It functions as a scaffold E3 promoting HR6B/UbcH2-dependent ubiquitylation of H2A and H2B, but not H3 and H4. It also binds to Tex19.1, also known as Tex19, a germ cell-specific protein, and metabolically stabilizes it during spermatogenesis. Furthermore, UBR2 is involved in skeletal muscle (SKM) atrophy. Its expression can be modulated by the mouse ether-a-gogo-related gene 1a (MERG1a) potassium channel. In addition, UBR2 up-regulation in cachectic muscle is mediated by the p38beta-CCAAT/enhancer binding protein (C/EBP)-beta signaling pathway responsible for the bulk of tumor-induced muscle proteolysis. UBR2 contains 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567 1107 TCILCQEEQEVTVGSRAMVLAAFVQRSTVLSKDRTKTIADPEKYDPLFMHPDLSCGTHTGSCGHVMHAHCWQRYFDSVQA 1186
Cdd:cd16686     1 TCILCQEEQEIKVDNKAMVLAAFVQRSTVMSKNRSRVIHDPEKYDPLFMHPDLSCGTHTGSCGHIMHAHCWQRYFDAVQA 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 293651567 1187 KEQRRQQRLRLHTSYDVENGEFLCPLCECLSNTVIP 1222
Cdd:cd16686    81 KEQRRQQRLRVHTSYDVENGEFLCPLCECLSNTVIP 116

ATP-dependent Clp protease adaptor protein ClpS; In the bacterial cytosol, ATP-dependent protein degradation is performed by several different chaperone-protease pairs, including ClpAP. ClpS directly influences the ClpAP machine by binding to the N-terminal domain of the chaperone ClpA. The degradation of ClpAP substrates, both SsrA-tagged proteins and ClpA itself, is specifically inhibited by ClpS. ClpS modifies ClpA substrate specificity, potentially redirecting degradation by ClpAP toward aggregated proteins.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 293651567   222 EKSDTYYCMLFNDEVHTYEQVIYTLQKAVNCTQKEAIGFATTVDRDGRRSVRYGDFQYCDQAKTVIVRNTSRQTKPLKV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARENGFPLRC 79

Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway; Domain is involved in recognition of N-end rule substrates in yeast Ubr1p

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                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567     98 LCGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHK 167
Cdd:smart00396    2 VCGYKFTGGEVIYRCKTCGLDPTCVLCSDCFRPSCHKGHDVSLKTSRGSGICDCGDKEAWNEDLKCKAHE 71

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-2 (UBR2) and similar proteins; UBR2, also known as N-recognin-2 or E3alpha-II, is an E3 ubiquitin-protein ligase that plays an important role in maintaining genome integrity and in homologous recombination repair. It regulates the level of the transcription factor Rpn4 (also known as Son1 and Ufd5) through ubiquitylation. The ubiquitin-conjugating enzyme Rad6, another binding partner of URB2, and an additional factor Mub1, are required for the ubiquitin-dependent degradation of Rpn4. UBR2 associates with Mub1 to form a Mub1/Ubr2 complex that regulates the conserved Dsn1 kinetochore protein levels, which is a part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability. As the recognition component of a major cellular proteolytic system, UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both spermatocytes and somatic cells. UBR2 also mediates transcriptional silencing during spermatogenesis via histone ubiquitination. It functions as a scaffold E3 promoting HR6B/UbcH2-dependent ubiquitylation of H2A and H2B, but not H3 and H4. It also binds to Tex19.1, also known as Tex19, a germ cell-specific protein, and metabolically stabilizes it during spermatogenesis. Furthermore, UBR2 is involved in skeletal muscle (SKM) atrophy. Its expression can be modulated by the mouse ether-a-gogo-related gene 1a (MERG1a) potassium channel. In addition, UBR2 up-regulation in cachectic muscle is mediated by the p38beta-CCAAT/enhancer binding protein (C/EBP)-beta signaling pathway responsible for the bulk of tumor-induced muscle proteolysis. UBR2 contains 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567 1107 TCILCQEEQEVTVGSRAMVLAAFVQRSTVLSKDRTKTIADPEKYDPLFMHPDLSCGTHTGSCGHVMHAHCWQRYFDSVQA 1186
Cdd:cd16686     1 TCILCQEEQEIKVDNKAMVLAAFVQRSTVMSKNRSRVIHDPEKYDPLFMHPDLSCGTHTGSCGHIMHAHCWQRYFDAVQA 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 293651567 1187 KEQRRQQRLRLHTSYDVENGEFLCPLCECLSNTVIP 1222
Cdd:cd16686    81 KEQRRQQRLRVHTSYDVENGEFLCPLCECLSNTVIP 116

UBR-box found in ubiquitin-protein ligase E3-alpha-2 (UBR2) and similar proteins; UBR2 (EC 2.3.2.27), also called ubiquitin-protein ligase E3-alpha-II (E3alpha-II), or N-recognin-2, is a RING-type E3 ubiquitin ligase of the Arg/N-end rule degradation pathway. It recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells. It plays an important role in spermatogenesis.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567   98 LCGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHK 167
Cdd:cd19679     1 LCGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHE 70

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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 293651567 1162 GTHTGSCGHVMHAHCWQRYFDSVQAKEQRRQQRLRLHtSYDVENGEFLCPLCECLSNTVIP 1222
Cdd:cd16482     8 GLHISSCGHVMHYDCWQRYFDSVRLREQRRPAFRRHH-SEDVSKGEFLCPLCKSLSNTVLP 67

ATP-dependent Clp protease adaptor protein ClpS; In the bacterial cytosol, ATP-dependent protein degradation is performed by several different chaperone-protease pairs, including ClpAP. ClpS directly influences the ClpAP machine by binding to the N-terminal domain of the chaperone ClpA. The degradation of ClpAP substrates, both SsrA-tagged proteins and ClpA itself, is specifically inhibited by ClpS. ClpS modifies ClpA substrate specificity, potentially redirecting degradation by ClpAP toward aggregated proteins.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 293651567   222 EKSDTYYCMLFNDEVHTYEQVIYTLQKAVNCTQKEAIGFATTVDRDGRRSVRYGDFQYCDQAKTVIVRNTSRQTKPLKV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARENGFPLRC 79

Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway; Domain is involved in recognition of N-end rule substrates in yeast Ubr1p

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 293651567     98 LCGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHK 167
Cdd:smart00396    2 VCGYKFTGGEVIYRCKTCGLDPTCVLCSDCFRPSCHKGHDVSLKTSRGSGICDCGDKEAWNEDLKCKAHE 71

UBR-box found in ubiquitin-protein ligase E3-alpha-1 (UBR1), E3-alpha-2 (UBR2), E3-alpha-3 (UBR3) and similar proteins; This family includes UBR1, UBR2, and UBR3 (all belonging to EC 2.3.2.27). Both UBR1 (also called E3alpha-I or N-recognin-1) and UBR2 (also called E3-alpha-II or N-recognin-2), are RING-type E3 ubiquitin ligases of the Arg/N-end rule degradation pathway. They recognize and bind to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Deficiency of UBR1 causes Johanson-Blizzard syndrome. UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells. It plays an important role in spermatogenesis. UBR3, also called ubiquitin-protein ligase E3-alpha-III (E3alpha-III), or N-recognin-3, or zinc finger protein 650, is a RING-type E3 ubiquitin ligase with a function in olfactory and other sensory systems. It negatively regulates the mono-ubiquitination of non-muscle Myosin II, a protein associated with hearing loss in humans. It acts as a positive regulator of Hedgehog (Hh) signaling in Drosophila and vertebrates. It also plays an important role for genome stability by controlling cellular levels of the essential DNA repair protein APE1.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 293651567   99 CGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHK 167
Cdd:cd19670     1 CGKSLKKGELYYRCLDCSLDPSSCICEECFLNGNHEGHNYSLRTSSGGGVCDCGDSEAWKPSGFCSKHQ 69

ATP-dependent Clp protease adapter protein ClpS [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 293651567  213 ELPEDLEVAEKSDTYYCMLFNDEVHTYEQVIYTLQKAVNCTQKEAIGFATTVDRDGR 269
Cdd:COG2127     7 PEEETETKTKPPPPYKVVLLNDDVNTMEFVVEVLQKVFGMSEEQAEQLMLEVHTKGK 63

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 293651567 1167 SCGHVMHAHCWQRYFDSVQA--KEQRRQQRLRLHTSYDVENGEFLCPLC 1213
Cdd:cd16470    22 PCYHYFHSHCLARYIQHMEEnlKEEQEEQEERPRAQTEQEQFQVLCPVC 70