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 154091026 1097 EVLTCILCQEEQEVKLENNAMVLSACVQKSTALTQHRGKPVDHLGETLDPLFMDPDLAHGTYTGSCGHVMHAVCWQKYFE 1176
Cdd:cd16685     1 EVLTCILCQEEQEVKLDKMAMVLTACVQKSTALTQNRGKVVELTGENFDPLFMNPDLAYGTHTGSCGHVMHAVCWQKYFE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 154091026 1177 AVQLSSQQRIHVDL-FDLESGEYLCPLCKSLCNTVIPIIP 1215
Cdd:cd16685    81 AVQNSTRQRLHVELiFDLENGEYLCPLCKSLCNTVIPIIP 120

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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026   221 EKNERYYCVLFNDEHHSYDHVIYSLQRALDCELAEAQLHTTAIDKEGRRAVKAGVYATCQEAKEDIKSHSENvSQHPLHV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARE-NGFPLRC 79

                   .
gi 154091026   301 E 301
Cdd:pfam02617   80 T 80

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-1 (UBR1) and similar proteins; UBR1, also known as N-recognin-1 or E3alpha-I, is an E3 ubiquitin-protein ligase component of the N-end rule pathway. It also promotes degradation of proteins via distinct mechanism that detects a misfolded conformation. UBR1 associates with the RAD6-encoded E2 enzyme to form an E2-E3 complex that catalyzes the synthesis of a substrate-linked multi-ubiquitin chain and may also mediate the delivery of substrates to the 26S proteasome. Moreover, UBR1 promotes the degradation of misfolded proteins in the cytosol. It promotes protein kinase quality control and sensitizes cells to heat shock protein 90 (Hsp90) inhibition. Furthermore, UBR1 functions as a polyubiquitylation-enhancing component of the UBR1-UFD4 complex in its targeting of ubiquitin-fusion degradation (UFD) substrates. UBR1 harbors at least three distinct substrate-binding sites and functions in association with Ubc2/Rad6 and also Ubc4. It 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. A missense mutation in UBR1 is responsible for Johanson-Blizzard syndrome leads to UBR box unfolding and loss of function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026 1097 EVLTCILCQEEQEVKLENNAMVLSACVQKSTALTQHRGKPVDHLGETLDPLFMDPDLAHGTYTGSCGHVMHAVCWQKYFE 1176
Cdd:cd16685     1 EVLTCILCQEEQEVKLDKMAMVLTACVQKSTALTQNRGKVVELTGENFDPLFMNPDLAYGTHTGSCGHVMHAVCWQKYFE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 154091026 1177 AVQLSSQQRIHVDL-FDLESGEYLCPLCKSLCNTVIPIIP 1215
Cdd:cd16685    81 AVQNSTRQRLHVELiFDLENGEYLCPLCKSLCNTVIPIIP 120

Putative zinc finger in N-recognin (UBR box); This region is found in E3 ubiquitin ligases that recognize N-recognins.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 154091026    99 CGKVFKSGETTYSCRDCAIDPTCVLCMDCFQSSVHKNHRYKMHTSTGGGFCDCGDTEAWKTGPFCVDH 166
Cdd:pfam02207    1 CGYVFKKGQPVYRCLTCSLDPTCVICYSCFINCDHEGHDYELFTSRGGGCCDCGDPEAWKEEGFCKLH 68

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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026   221 EKNERYYCVLFNDEHHSYDHVIYSLQRALDCELAEAQLHTTAIDKEGRRAVKAGVYATCQEAKEDIKSHSENvSQHPLHV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARE-NGFPLRC 79

                   .
gi 154091026   301 E 301
Cdd:pfam02617   80 T 80

ATP-dependent Clp protease adaptor protein ClpS; Reviewed

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026  218 QIREKNERYYCVLFNDEHHSYDHVIYSLQR--ALDCELAEA---QLHTtaidkEGRravkaGVYATCqeAKEDIKSHSEN 292
Cdd:PRK00033   20 PKLKPPPMYKVLLHNDDYTPMEFVVYVLQKffGYDRERATQimlEVHN-----EGK-----AVVGVC--TREVAETKVEQ 87

                  ....*.
gi 154091026  293 VSQHPL 298
Cdd:PRK00033   88 VHQHGL 93

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-1 (UBR1) and similar proteins; UBR1, also known as N-recognin-1 or E3alpha-I, is an E3 ubiquitin-protein ligase component of the N-end rule pathway. It also promotes degradation of proteins via distinct mechanism that detects a misfolded conformation. UBR1 associates with the RAD6-encoded E2 enzyme to form an E2-E3 complex that catalyzes the synthesis of a substrate-linked multi-ubiquitin chain and may also mediate the delivery of substrates to the 26S proteasome. Moreover, UBR1 promotes the degradation of misfolded proteins in the cytosol. It promotes protein kinase quality control and sensitizes cells to heat shock protein 90 (Hsp90) inhibition. Furthermore, UBR1 functions as a polyubiquitylation-enhancing component of the UBR1-UFD4 complex in its targeting of ubiquitin-fusion degradation (UFD) substrates. UBR1 harbors at least three distinct substrate-binding sites and functions in association with Ubc2/Rad6 and also Ubc4. It 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. A missense mutation in UBR1 is responsible for Johanson-Blizzard syndrome leads to UBR box unfolding and loss of function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026 1097 EVLTCILCQEEQEVKLENNAMVLSACVQKSTALTQHRGKPVDHLGETLDPLFMDPDLAHGTYTGSCGHVMHAVCWQKYFE 1176
Cdd:cd16685     1 EVLTCILCQEEQEVKLDKMAMVLTACVQKSTALTQNRGKVVELTGENFDPLFMNPDLAYGTHTGSCGHVMHAVCWQKYFE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 154091026 1177 AVQLSSQQRIHVDL-FDLESGEYLCPLCKSLCNTVIPIIP 1215
Cdd:cd16685    81 AVQNSTRQRLHVELiFDLENGEYLCPLCKSLCNTVIPIIP 120

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 154091026 1100 TCILCQEEQEVKLENNAMVLSACVQKSTALTQHRGKPVdHLGETLDPLFMDPDLAHGTYTGSCGHVMHAVCWQKYFEAVQ 1179
Cdd:cd16686     1 TCILCQEEQEIKVDNKAMVLAAFVQRSTVMSKNRSRVI-HDPEKYDPLFMHPDLSCGTHTGSCGHIMHAHCWQRYFDAVQ 79

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 154091026 1180 LSSQQ-----RIHVDlFDLESGEYLCPLCKSLCNTVIP 1212
Cdd:cd16686    80 AKEQRrqqrlRVHTS-YDVENGEFLCPLCECLSNTVIP 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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026   98 LCGKVFKSGETTYSCRDCAIDPTCVLCMDCFQSSVHKNHRYKMHTSTGGGFCDCGDTEAWKTGPFCVDHE 167
Cdd:cd19679     1 LCGRVFKVGEPTYSCRDCAVDPTCVLCMECFLGSIHRDHRYRMTTSGGGGFCDCGDTEAWKEGPYCQKHE 70

UBR-box found in ubiquitin-protein ligase E3-alpha-3 (UBR3) and similar proteins; UBR3 (EC 2.3.2.27), 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 154091026   99 CGKVFKSGETTYSCRDCAIDPTCVLCMDCFQSSVHKNHRYKMHTSTGGGFCDCGDTEAWKTGPFCVDH 166
Cdd:cd19673     4 CGRVWKAGDIAYRCRTCGLDPTCVICADCFQAGDHEGHDYSMYRSSAGGCCDCGDPEAWKPSGFCSRH 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 154091026   99 CGKVFKSGETTYSCRDCAIDPTCVLCMDCFQSSVHKNHRYKMHTSTGGGFCDCGDTEAWKTGPFCVDH 166
Cdd:cd19670     1 CGKSLKKGELYYRCLDCSLDPSSCICEECFLNGNHEGHNYSLRTSSGGGVCDCGDSEAWKPSGFCSKH 68

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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026   221 EKNERYYCVLFNDEHHSYDHVIYSLQRALDCELAEAQLHTTAIDKEGRRAVKAGVYATCQEAKEDIKSHSENvSQHPLHV 300
Cdd:pfam02617    1 KEPPMYKVILLNDDYTTMEFVVEVLQRVFGKSEEEATEIMLQVHREGRAVVGVYTYDIAETKVAQVHQLARE-NGFPLRC 79

                   .
gi 154091026   301 E 301
Cdd:pfam02617   80 T 80

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-3 (UBR3) and similar proteins; UBR3, also known as N-recognin-3, E3alpha-III, or zinc finger protein 650, is an E3 ubiquitin-protein ligase targeting the essential DNA repair protein APE1, also known as Ref-1, for ubiquitylation. It regulates cellular levels of APE1 and is required for genome stability. It also plays a regulatory role in sensory pathways, including olfaction. In Drosophila, UBR3 also regulates apoptosis by controlling the activity of Drosophila inhibitor of apoptosis protein 1 (DIAP1), which is required to prevent caspase activation. UBR3 contains an N-terminal ubiquitin-recognin (UBR) box, a C3H2C3-type RING-H2 finger, and a C-terminal UBR-specific autoinhibitory (UAIN) domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 154091026 1156 GTYTGSCGHVMHAVCWQKYFEAVQlssQQRIHVDLFDLESGEYLCPLCKSLCNTVIP 1212
Cdd:cd16483    10 GVHVQTCGHYIHIDCHKSYLESLR---QDQVGLQLLSVRRGEFTCPLCRQLSNSVLP 63

ATP-dependent Clp protease adaptor protein ClpS; Reviewed

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 154091026  218 QIREKNERYYCVLFNDEHHSYDHVIYSLQR--ALDCELAEA---QLHTtaidkEGRravkaGVYATCqeAKEDIKSHSEN 292
Cdd:PRK00033   20 PKLKPPPMYKVLLHNDDYTPMEFVVYVLQKffGYDRERATQimlEVHN-----EGK-----AVVGVC--TREVAETKVEQ 87

                  ....*.
gi 154091026  293 VSQHPL 298
Cdd:PRK00033   88 VHQHGL 93