HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168  81 EPGCIWTLINMAYCVLILLGKSIQKLVFGELRVSERQHLKDKFWNFIFyKFIFVFGVLNVQYMDEVVLWcawFTALGFLS 160
Cdd:COG5243   39 SPVHITIGLNVILLLFFLIANALKTLLFGSLRTFELELLYEQLWITLT-EILLAISVFREAISFSFFML---LSTLLFAK 114

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 161 LLSQLCKDRFEYLSF-SPTTPGWSHARLLGLLTAILALSSFMLLLCFAAAFFFVSFNTFAFMAAECILLGVRTIhVMLRY 239
Cdd:COG5243  115 VFHWILSFRTERLQIqSTDQRFHIFSRFSCAYFLLSILDASLIYLCISSEHLIDKSTLFLFVCEFSVLLLNLTS-EANKL 193

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 240 AIHLYDTRGAGtssprswDKRGSLAYYTELASE-LTVLAVDLLHHIHMLLWSNIFLSMASLVICmqlrylFHEIQRRITK 318
Cdd:COG5243  194 CVYNYEARDDD-------DERSTYLFRLEVCYDgLTLLAYSLLFMYQFPYVRVPIYLIRQMYTC------FYALFRRIRE 260

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 319 HRNYLAVLNHMEQNYPMASAEELAENSDNCAICWEKM-------------DSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:COG5243  261 HARFRRATKDLNAMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC 340

                        330
                 ....*....|....*...
gi 817193168 386 RqaLSMQANHRESTPEIP 403
Cdd:COG5243  341 R--RPVIFDQSSPTPASP 356

E3 gp78 Ube2g2-binding region (G2BR); The activity of RING finger ubiquitin ligases (E3) is dependent on their ability to facilitate transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to substrates. The G2BR domain within the E3 gp78 binds selectively and with high affinity to the E2 Ube2g2. Binding to the G2BR results in conformational changes in Ube2g2 that affect ubiquitin loading. The Ube2g2-G2BR interaction also causes a 50-fold increase in affinity between the E2 and RING finger. Hence, the Ube2g2-binding region (G2BR) is required for the function of gp78. In yeast, Ubc7p, the ortholog of Ube2g2, is recruited by Cue1p to the ER membrane. Cue1p directly binds Ubc7p through a stretch of 50 aa domain analogous to G2BR, i.e. suggesting that this domain which activates ERAD and Hrd1p stimulating ubiquitylation, might be the yeast equivalent of the G2BR domain.

                          10        20
                  ....*....|....*....|....
gi 817193168  551 ERERILRRRKEHMLLTARRKYLEK 574
Cdd:pfam18442   3 ERQRMLVQRKEELLQQARRRYLNK 26

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168  81 EPGCIWTLINMAYCVLILLGKSIQKLVFGELRVSERQHLKDKFWNFIFyKFIFVFGVLNVQYMDEVVLWcawFTALGFLS 160
Cdd:COG5243   39 SPVHITIGLNVILLLFFLIANALKTLLFGSLRTFELELLYEQLWITLT-EILLAISVFREAISFSFFML---LSTLLFAK 114

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 161 LLSQLCKDRFEYLSF-SPTTPGWSHARLLGLLTAILALSSFMLLLCFAAAFFFVSFNTFAFMAAECILLGVRTIhVMLRY 239
Cdd:COG5243  115 VFHWILSFRTERLQIqSTDQRFHIFSRFSCAYFLLSILDASLIYLCISSEHLIDKSTLFLFVCEFSVLLLNLTS-EANKL 193

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 240 AIHLYDTRGAGtssprswDKRGSLAYYTELASE-LTVLAVDLLHHIHMLLWSNIFLSMASLVICmqlrylFHEIQRRITK 318
Cdd:COG5243  194 CVYNYEARDDD-------DERSTYLFRLEVCYDgLTLLAYSLLFMYQFPYVRVPIYLIRQMYTC------FYALFRRIRE 260

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 319 HRNYLAVLNHMEQNYPMASAEELAENSDNCAICWEKM-------------DSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:COG5243  261 HARFRRATKDLNAMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC 340

                        330
                 ....*....|....*...
gi 817193168 386 RqaLSMQANHRESTPEIP 403
Cdd:COG5243  341 R--RPVIFDQSSPTPASP 356

CUE domain found in autocrine motility factor receptor (AMFR) and similar proteins; AMFR is an internalizing cell surface glycoprotein that is localized in both plasma membrane caveolae and the endoplasmic reticulum (ER), and involves in the regulation of cellular adhesion, proliferation, motility and apoptosis, as well as in the process of learning and memory. It is also called ER-protein gp78 that has been identified as a RING finger-dependent ubiquitin protein ligase (E3) implicated in degradation from the ER. AMFR contains an N-terminal RING-finger domain and a C-terminal CUE domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 817193168 456 DAMARQVQQLFPHYPRNIVLEDLRVTRSVELTIENILDGRL 496
Cdd:cd14421    1 DAMAHQVQEMFPQVPLSVILADLRLTRSVEVTIENILEGRL 41

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 817193168   348 CAICWEKM-DSARKLPCGHLFHNSCLQSWLEQDT-SCPTC 385
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGNnTCPIC 40

Domain that may be involved in binding ubiquitin-conjugating enzymes (UBCs); CUE domains also occur in two protein of the IL-1 signal transduction pathway, tollip and TAB2. Ponting (Biochem. J.) "Proteins of the Endoplasmic reticulum" (in press)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 817193168   454 QLDAMARQVQQLFPHYPRNIVLEDLRV-TRSVELTIENILDGR 495
Cdd:smart00546   1 ENDEALHDLKEMFPNLDEEVIEAVLEAnTGNVEATINNLLEGS 43

E3 gp78 Ube2g2-binding region (G2BR); The activity of RING finger ubiquitin ligases (E3) is dependent on their ability to facilitate transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to substrates. The G2BR domain within the E3 gp78 binds selectively and with high affinity to the E2 Ube2g2. Binding to the G2BR results in conformational changes in Ube2g2 that affect ubiquitin loading. The Ube2g2-G2BR interaction also causes a 50-fold increase in affinity between the E2 and RING finger. Hence, the Ube2g2-binding region (G2BR) is required for the function of gp78. In yeast, Ubc7p, the ortholog of Ube2g2, is recruited by Cue1p to the ER membrane. Cue1p directly binds Ubc7p through a stretch of 50 aa domain analogous to G2BR, i.e. suggesting that this domain which activates ERAD and Hrd1p stimulating ubiquitylation, might be the yeast equivalent of the G2BR domain.

                          10        20
                  ....*....|....*....|....
gi 817193168  551 ERERILRRRKEHMLLTARRKYLEK 574
Cdd:pfam18442   3 ERQRMLVQRKEELLQQARRRYLNK 26

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168  81 EPGCIWTLINMAYCVLILLGKSIQKLVFGELRVSERQHLKDKFWNFIFyKFIFVFGVLNVQYMDEVVLWcawFTALGFLS 160
Cdd:COG5243   39 SPVHITIGLNVILLLFFLIANALKTLLFGSLRTFELELLYEQLWITLT-EILLAISVFREAISFSFFML---LSTLLFAK 114

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 161 LLSQLCKDRFEYLSF-SPTTPGWSHARLLGLLTAILALSSFMLLLCFAAAFFFVSFNTFAFMAAECILLGVRTIhVMLRY 239
Cdd:COG5243  115 VFHWILSFRTERLQIqSTDQRFHIFSRFSCAYFLLSILDASLIYLCISSEHLIDKSTLFLFVCEFSVLLLNLTS-EANKL 193

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 240 AIHLYDTRGAGtssprswDKRGSLAYYTELASE-LTVLAVDLLHHIHMLLWSNIFLSMASLVICmqlrylFHEIQRRITK 318
Cdd:COG5243  194 CVYNYEARDDD-------DERSTYLFRLEVCYDgLTLLAYSLLFMYQFPYVRVPIYLIRQMYTC------FYALFRRIRE 260

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 319 HRNYLAVLNHMEQNYPMASAEELAENSDNCAICWEKM-------------DSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:COG5243  261 HARFRRATKDLNAMYPTATEEQLTNSDRTCTICMDEMfhpdheplprgldMTPKRLPCGHILHLHCLKNWLERQQTCPIC 340

                        330
                 ....*....|....*...
gi 817193168 386 RqaLSMQANHRESTPEIP 403
Cdd:COG5243  341 R--RPVIFDQSSPTPASP 356

CUE domain found in autocrine motility factor receptor (AMFR) and similar proteins; AMFR is an internalizing cell surface glycoprotein that is localized in both plasma membrane caveolae and the endoplasmic reticulum (ER), and involves in the regulation of cellular adhesion, proliferation, motility and apoptosis, as well as in the process of learning and memory. It is also called ER-protein gp78 that has been identified as a RING finger-dependent ubiquitin protein ligase (E3) implicated in degradation from the ER. AMFR contains an N-terminal RING-finger domain and a C-terminal CUE domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 817193168 456 DAMARQVQQLFPHYPRNIVLEDLRVTRSVELTIENILDGRL 496
Cdd:cd14421    1 DAMAHQVQEMFPQVPLSVILADLRLTRSVEVTIENILEGRL 41

RING finger, H2 subclass, found in RING finger proteins RNF126, RNF115, and similar proteins; This subfamily includes RING finger proteins RNF126, RNF115, and similar proteins. RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. RNF115, also known as Rab7-interacting ring finger protein (Rabring 7), or zinc finger protein 364 (ZNF364), or breast cancer-associated gene 2 (BCA2), is an E3 ubiquitin-protein ligase that is an endogenous inhibitor of adenosine monophosphate-activated protein kinase (AMPK) activation; this inhibition increases the efficacy of metformin in breast cancer cells. It also functions as a cofactor in the restriction imposed by tetherin on HIV-1, and targets HIV-1 Gag for lysosomal degradation, impairing virus assembly and release, in a tetherin-independent manner. Moreover, RNF115 is a Rab7-binding protein that stimulates c-Myc degradation through mono-ubiquitination of MM-1. It also plays crucial roles as a Rab7 target protein in vesicle traffic to late endosome/lysosome and lysosome biogenesis. RNF115 and RNF126 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. Both of them contain an N-terminal BCA2 Zinc-finger domain (BZF), AKT-phosphorylation sites, and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 817193168 347 NCAICWEKM---DSARKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16667    1 ECAVCKEDFevgEEVRQLPCKHLFHPDCIVPWLELHNSCPVCR 43

H2 subclass of RING (RING-H2) fingers 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 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). This family corresponds to the H2 subclass of RING (RING-H2) finger proteins that are characterized by containing C3H2C3-type canonical RING-H2 fingers or noncanonical RING-H2 finger variants, including C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type modified RING-H2 fingers. The canonical RING-H2 finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, X is any amino acid and the number of X residues varies in different fingers. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-H2 finger 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 serves as a scaffold 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 817193168 348 CAICWEKMDS---ARKLPCGHLFHNSCLQSWLE-QDTSCPTCR 386
Cdd:cd16448    1 CVICLEEFEEgdvVRLLPCGHVFHLACILRWLEsGNNTCPLCR 43

RING finger, H2 subclass, found in RING finger protein 126 (RNF126) and similar proteins; RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). Moreover, RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. In addition, RNF126 and the related protein, RNF115 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF126 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 817193168 348 CAICWEKM---DSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQ 387
Cdd:cd16801    2 CPVCKEDYtvgENVRQLPCNHLFHNDCIVPWLEQHDTCPVCRK 44

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 817193168 347 NCAICWEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALSM 391
Cdd:cd16561    4 ECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMSCPLCRTELPD 48

CUE domain found in ancient ubiquitous protein 1 (AUP1), autocrine motility factor receptor (AMFR) and similar proteins; AUP1 is a component of the HRD1-SEL1L endoplasmic reticulum (ER) quality control complex and is essential for US11-mediated dislocation of class I MHC heavy chains. AMFR is an internalizing cell surface glycoprotein that is localized in both plasma membrane caveolae and the ER, and involves in the regulation of cellular adhesion, proliferation, motility and apoptosis, as well as in the process of learning and memory. Cue1p is an N-terminally membrane-anchored endoplasmic reticulum (ER) protein essential for the activity of the two major yeast RING finger ubiquitin ligases (E3s) implicated in ER-associated degradation (ERAD). This family also includes plant E3 ubiquitin protein ligases RIN2, RIN3, and similar proteins. Comparing with other CUE domain-containing proteins, some family members from higher eukaryotes do not bind monoubiquitin efficiently, since they carry LP, rather than FP among CUE domains.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 817193168 456 DAMARQVQQLFPHYPRNIVLEDLRVTRSVELTIENIL 492
Cdd:cd14376    1 EEMVEQVQEVFPHIPREAIRRDLQRTNSVDLTINNIL 37

RING finger, H2 subclass, found in protein E3 ubiquitin-protein ligase Praja-1, Praja-2, and similar proteins; This family includes two highly similar E3 ubiquitin-protein ligases, Praja-1 and Praja-2. Praja-1, also known as RING finger protein 70, is a RING-H2 finger ubiquitin ligase encoded by gene PJA1, a novel human X chromosome gene abundantly expressed in the brain. It has been implicated in bone and liver development, as well as memory formation and X-linked mental retardation (MRX). Praja-1 interacts with and activates the ubiquitin-conjugating enzyme UbcH5B, and shows E2-dependent E3 ubiquitin ligase activity. It is a 3-deazaneplanocin A (DZNep)-induced ubiquitin ligase that directly ubiquitinates individual polycomb repressive complex 2 (PRC2) subunits in a cell free system, which leads to their proteasomal degradation. It also plays an important role in neuronal plasticity, which is the basis for learning and memory. Moreover, Praja-1 ubiquitinates embryonic liver fodrin (ELF) and Smad3, but not Smad4, in a transforming growth factor-beta (TGF-beta)-dependent manner. It controls ELF abundance through ubiquitin-mediated degradation, and further regulates TGF-beta signaling, which plays a key role in the suppression of gastric carcinoma. Praja-1 also regulates the transcription function of the homeodomain protein Dlx5 by controlling the stability of Dlxin-1, via a ubiquitin-dependent degradation pathway. Praja-2, also known as RING finger protein 131, NEURODAP1, or KIAA0438, is an E2-dependent E3 ubiquitin ligase that interacts with and activates the ubiquitin-conjugating enzyme UbcH5B. It functions as an A-kinase anchoring protein (AKAP)-like E3 ubiquitin ligase that plays a critical role in controlling cyclic AMP (cAMP)-dependent PKA activity and pro-survival signaling, and further promotes cell proliferation and growth. Praja-2 is also involved in protein sorting at the postsynaptic density region of axosomatic synapses and possibly plays a role in synaptic communication and plasticity. Together with the AMPK-related kinase SIK2 and the CDK5 activator CDK5R1/p35, it forms a SIK2-p35-PJA2 complex that plays an essential role for glucose homeostasis in pancreatic beta cell functional compensation. Praja-2 ubiquitylates and degrades Mob, a core component of NDR/LATS kinase and a positive regulator of the tumor-suppressor Hippo signaling. Both Praja-1 and Praja-2 contain a potential nuclear localization signal (NLS) and a C-terminal C3H2C3-type RING-H2 motif.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 817193168 348 CAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQAL 389
Cdd:cd16465    2 CPICcseYVKDEIATELPCHHLFHKPCITAWLQKSGTCPVCRHVL 46

RING finger, H2 subclass, found in TRAF-interacting protein (TRAIP) and similar proteins; TRAIP, also known as RING finger protein 206 (RNF206) or TRIP, is a ubiquitously expressed nucleolar E3 ubiquitin ligase important for cellular proliferation and differentiation. It is found near mitotic chromosomes and functions as a regulator of the spindle assembly checkpoint. TRAIP interacts with tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins and inhibits TNF-alpha-mediated nuclear factor (NF)-kappaB activation. It also interacts with two tumor suppressors CYLD and spleen tyrosine kinase (Syk), and DNA polymerase eta, which facilitates translesional synthesis after DNA damage. TRAIP contains an N-terminal C3H2C2-type RING-H2 finger and an extended coiled-coil domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 817193168 347 NCAICWEKMDSARKL---PCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16480    1 YCTICSDFFDNSRDVaaiHCGHTFHYDCLLQWFDTSRTCPQCR 43

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 817193168 345 SDNCAICWEKM---DSARKLPCGHLFHNSCLQSWLEQD-TSCPTCRQALSM 391
Cdd:cd16473    4 CEECAICLENYqngDLLRGLPCGHVFHQNCIDVWLERDnHCCPVCRWPVYK 54

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
                 ....*....|....*....|....*....|....*....|...
gi 817193168 346 DNCAICWE---KMDSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:cd16469    1 DTCAVCLEefkLKEELGVCPCGHAFHTKCLKKWLEVRNSCPIC 43

RING finger, H2 subclass, found in BRCA1-associated protein (BRAP2) and similar proteins; BRAP2, also known as impedes mitogenic signal propagation (IMP), RING finger protein 52, or renal carcinoma antigen NY-REN-63, is a novel cytoplasmic protein interacting with the two functional nuclear localization signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin. BRAP2 serves as a cytoplasmic retention protein and plays a role in the regulation of nuclear protein transport. It contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), followed by a C3H2C3-type RING-H2 finger and a UBP-type zinc finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 817193168 347 NCAICWEKMDSARK----LPCGHLFHNSCLQSWleQDTSCPTCR 386
Cdd:cd16457    2 TCPVCLERMDESVSgiltILCNHSFHCSCLSKW--GDSSCPVCR 43

RING finger, H2 subclass, found in RING finger protein 130 (RNF130) and similar proteins; RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL). It is a transmembrane E3 ubiquitin-protein ligase expressed in leukocytes. It has a self-ubiquitination property, and controls the development of T cell clonal anergy by ubiquitination. RNF130 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 817193168 346 DNCAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16803    1 DHCAVCiegYKQNDVVRILPCKHVFHKSCVDPWLNEHCTCPMCK 44

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 817193168 339 EELAENSDNCAICW---EKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALSMQ 392
Cdd:cd16682    1 GEESDTDEKCTICLsmlEDGEDVRRLPCMHLFHQLCVDQWLAMSKKCPICRVDIETQ 57

RING finger, H2 subclass, found in E3 ubiquitin-protein ligase RNF6, RNF12, and similar proteins; RNF6 is an androgen receptor (AR)-associated protein that induces AR ubiquitination and promotes AR transcriptional activity. RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity by modulating cofactor recruitment. RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. RNF6 also regulates local serine/threonine kinase LIM kinase 1 (LIMK1) levels in axonal growth cones. RNF6-induced LIMK1 polyubiquitination is mediated via K48 of ubiquitin and leads to proteasomal degradation of the kinase. RNF6 binds and upregulates the Inha promoter, and functions as a transcription regulatory protein in the mouse sertoli cell. It acts as a potential tumor suppressor gene involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). RNF12, also known as LIM domain-interacting RING finger protein, or RING finger LIM domain-binding protein (R-LIM), is an E3 ubiquitin-protein ligase encoded by gene RLIM that is crucial for normal embryonic development in some species and for normal X inactivation in mice. It thus functions as a major sex-specific epigenetic regulator of female mouse nurturing tissues. RNF12 is widely expressed during embryogenesis, and mainly localizes to the cell nucleus, where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7, and REX1, by proteasomal degradation. Both RNF6 and RNF12 contain a well conserved C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 817193168 348 CAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16467    2 CTIClgeYETGEKLRRLPCSHEFHSECVDRWLKENSSCPICR 43

RING finger, H2 subclass, found in RING finger protein 145 (RNF145) and similar proteins; RNF145 is an uncharacterized RING finger protein encoded by the RNF145 gene, which is expressed in T lymphocytes, and its expression is altered in acute myelomonocytic and acute promyelocytic leukemias. Although its biological function remains unclear, RNF145 shows high sequence similarity with RNF139, an endoplasmic reticulum (ER)-resident multi-transmembrane protein that functions as a potent growth suppressor in mammalian cells, inducing G2/M arrest, decreased DNA synthesis and increased apoptosis. Like RNF139, RNF145 contains a C3H2C3-type RING-H2 finger with possible E3-ubiquitin ligase activity.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 817193168 344 NSDNCAICWEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:cd16684    1 HNDICSICYQDMKSAVITPCSHFFHAGCLKKWLYVQETCPLC 42

RING finger, H2 subclass, found in Arabidopsis thaliana RING-type E3 ubiquitin transferase BIG BROTHER (BB) and similar proteins; BB (also known as protein ENHANCER OF DA1-1 or EOD1) is an E3 ubiquitin-protein ligase that limits organ size, and possibly seed size, in a dose-dependent manner. It negatively regulates the duration of cell proliferation in leaves and petals independently of the major phytohormones (e.g. auxin, cytokinin, gibberellin, brassinosteroids, ethylene, abscisic acid, jasmonic acid), probably by targeting growth stimulators for degradation. It limits the proliferation of root meristematic cells. BB polyubiquitinates DA1. It is involved in the promotion of leaf senescence, in addition to its function in restricting plant growth. BB-related is an E3 ubiquitin-ligase probably involved in organ size regulation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 817193168 342 AENSDNCAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:cd23115    1 DEDNERCVICrleYEEGEDLLTLPCKHCYHSECIQQWLQINKVCPVC 47

RING finger, HC subclass, found in Equid alphaherpesvirus 1 (Equine herpesvirus 1/EHV-1) regulatory protein and similar proteins; EHV-1 regulatory protein belongs to the Vmw110 (IPC0) protein family. It contains a typical C3HC4-type RING-HC finger and binds zinc stably.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 817193168 346 DNCAICWEKM-DSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALS 390
Cdd:cd23130    1 DVCPICLDDPeDEAITLPCLHQFCYTCILRWLQTSPTCPLCKTPVT 46

RING finger, H2 subclass, found in RING finger protein 12 (RNF12) and similar proteins; RNF12, also known as LIM domain-interacting RING finger protein or RING finger LIM domain-binding protein (R-LIM), is an E3 ubiquitin-protein ligase encoded by gene RLIM that is crucial for normal embryonic development in some species and for normal X inactivation in mice. It thus functions as a major sex-specific epigenetic regulator of female mouse nurturing tissues. RNF12 is widely expressed during embryogenesis, and mainly localizes to the cell nucleus, where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7, and REX1, by proteasomal degradation. Its functional activity is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. It is negatively regulated by pluripotency factors in embryonic stem cells. p53 represses its transcription through Sp1. RNF12 is the primary factor responsible for X chromosome inactivation (XCI) in female placental mammals. It is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI. It also targets REX1, an inhibitor of XCI, for proteasomal degradation. RNF12 also acts as a co-regulator for a range of transcription factors, particularly those containing a LIM homeodomain, and modulates the formation of transcriptional multiprotein complexes. It is a negative regulator of Smad7, which in turn negatively regulates the signaling of type I receptors from the transforming growth factor beta (TGF-beta) superfamily. In addition, paternal RNF12 is a critical survival factor for milk-producing alveolar cells. RNF12 contains an nuclear localization signal (NLS) and a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 817193168 348 CAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQAL 389
Cdd:cd16674    3 CSVCiteYTEGNKLRKLPCSHEYHVHCIDRWLSENSTCPICRRAV 47

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 817193168 348 CAICWEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALSMQ 392
Cdd:cd16527    3 CSLCLEERRHPTATPCGHLFCWSCITEWCNEKPECPLCREPFQPQ 47

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 817193168 348 CAIC---WEKMDSARKLP-CGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16461    2 CAIClsdYENGEELRRLPeCKHAFHKECIDEWLKSNSTCPLCR 44

RING finger, H2 subclass, found in RING finger protein 11 (RNF11) and similar proteins; RNF11 is an E3 ubiquitin-protein ligase that acts both as an adaptor and a modulator of itch-mediated control of ubiquitination events underlying membrane traffic. It acts downstream of an enzymatic cascade for the ubiquitination of specific substrates. It is also a molecular adaptor of homologous to E6-associated protein C-terminus (HECT)-type ligases. RNF11 has been implicated in the regulation of several signaling pathways. It enhances transforming growth factor receptor (TGFR) signaling by both abrogating Smurf2-mediated receptor ubiquitination and by promoting the Smurf2-mediated degradation of AMSH (associated molecule with the SH3 domain of STAM), a de-ubiquitinating enzyme that enhances TGF-beta signaling and epidermal growth factor receptor (EGFR) endosomal recycling. It also acts directly on Smad4 to enhance Smad4 function, and plays a role in prolonged TGF-beta signaling. RNF11 also functions as a critical component of the A20 ubiquitin-editing protein complex that negatively regulates tumor necrosis factor (TNF)-mediated nuclear factor (NF)-kappaB activation. It interacts with Smad anchor for receptor activation (SARA) and the endosomal sorting complex required for transport (ESCRT)-0 complex, thus participating in the regulation of lysosomal degradation of EGFR. RNF11 acts as a novel GGA cargo actively participating in regulating the ubiquitination of the GGA protein family. RNF11 functions together with TAX1BP1 to target TANK-binding kinase 1 (TBK1)/IkappaB kinase IKKi, and further restricts antiviral signaling and type I interferon (IFN)-beta production. RNF11 contains an N-terminal PPPY motif that binds WW domain-containing proteins such as AIP4/itch, Nedd4 and Smurf1/2 (SMAD-specific E3 ubiquitin-protein ligase 1/2), and a C-terminal C3H2C3-type RING-H2 finger that functions as a scaffold for the coordinated transfer of ubiquitin to substrate proteins together with the E2 enzymes UbcH527 and Ubc13.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 817193168 347 NCAICWEKM---DSARKLPCGHLFHNSCLQSWLEQDTSCPTC 385
Cdd:cd16468    1 ECVICMADFvvgDPIRYLPCMHIYHVDCIDDWLMRSFTCPSC 42

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 817193168 344 NSDNCAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16472    1 DQTQCVVCmcdYEKRQLLRVLPCSHEFHAKCIDKWLKTNRTCPICR 46

RING finger, H2 subclass, found in Saccharomyces cerevisiae transmembrane E3 ubiquitin-protein ligase 1 (TUL1) and similar proteins; This subfamily includes Saccharomyces cerevisiae TUL1, Schizosaccharomyces pombe DSC E3 ubiquitin ligase complex subunit 1 (DSC1), and Arabidopsis thaliana protein FLYING SAUCER 2 (FLY2). TUL1 is the catalytic component of DSC E3 ubiquitin ligase complexes that tag proteins present in Golgi, endosome and vacuole membranes and function in protein homeostasis under non-stress conditions, and support a role in protein quality control. It mediates ubiquitination of vacuolar proteins such as CPS1, PPN1, PEP12 and other proteins containing exposed hydrophilic residues within their transmembrane domains, leading to their sorting into internal vesicles in late endosomes. TUL1 also targets the unpalmitoylated endosomal SNARE TLG1 to the multivesicular body (MVB) pathway. DSC1, also known as defective for SREBP cleavage protein 1, is the catalytic component of the DSC E3 ubiquitin ligase complex required for the sre1 transcriptional activator proteolytic cleavage to release the soluble transcription factor from the membrane in low oxygen or sterol conditions. FLY2 acts as an E3 ubiquitin-protein ligase that may be involved in xylem development. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 817193168 348 CAICWEKMD-----SARK----LPCGHLFHNSCLQSWLEQDTSCPTCRQALSM 391
Cdd:cd23117    7 CVICMSDIElpstnSVRRdymvTPCNHIFHTNCLERWMDIKLECPTCRRPLPP 59

RING finger, H2 subclass, found in E3 ubiquitin-protein ligase RNF6 and similar proteins; RNF6 is an androgen receptor (AR)-associated protein that induces AR ubiquitination and promotes AR transcriptional activity. RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity by modulating cofactor recruitment. RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. Moreover, RNF6 regulates local serine/threonine kinase LIM kinase 1 (LIMK1) levels in axonal growth cones. RNF6-induced LIMK1 polyubiquitination is mediated via K48 of ubiquitin and leads to proteasomal degradation of the kinase. RNF6 also binds and upregulates the Inha promoter, and functions as a transcription regulatory protein in the mouse sertoli cell. RNF6 also acts as a potential tumor suppressor gene involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). RNF6 contains an N-terminal coiled-coil domain, a Lys-X-X-Leu/Ile-X-X-Leu/Ile (KIL) motif, and a C-terminal C3H2C3-type RING-H2 finger which is responsible for its ubiquitin ligase activity. The KIL motif is present in a subset of RING-H2 proteins from organisms as evolutionarily diverse as human, mouse, chicken, Drosophila, Caenorhabditis elegans, and Arabidopsis thaliana.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 817193168 348 CAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALS 390
Cdd:cd16673    3 CSVCineYATGNKLRRLPCAHEFHIHCIDRWLSENSTCPICRQPVL 48

RING finger, H2 subclass, found in RING finger protein 13 (RNF13) and similar proteins; RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that is functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. It functions as an important regulator of inositol-requiring transmembrane kinase/endonuclease IRE1alpha, mediating endoplasmic reticulum (ER) stress-induced apoptosis through the activation of the IRE1alpha-TRAF2-JNK signaling pathway. Moreover, RNF13 is involved in the regulation of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex via the ubiquitination of snapin, a SNAP25-interacting protein, which thereby controls synaptic function. In addition, RNF13 participates in regulating the function of satellite cells by modulating cytokine composition. RNF13 is evolutionarily conserved among many metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 817193168 346 DNCAIC---WEKMDSARKLPCGHLFHNSCLQSWLEQ-DTSCPTCRQ 387
Cdd:cd16796    9 DVCAICldeYEEGDKLRILPCSHAYHCKCVDPWLTKtKKTCPVCKQ 54

RING finger, HC subclass, found in RING finger and transmembrane domain-containing protein 2(RNFT2); RNFT2, also known as transmembrane protein 118 (TMEM118), is a multi-pass membrane protein containing a C3HC4-type RING-HC finger. Its biological role remains unclear.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 817193168 336 ASAEELAENSDNCAICWEKMDSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQA 388
Cdd:cd16742    4 ATSQQCSEAGDICAICQAEFREPLILICQHVFCEECLCLWFDRERTCPLCRSV 56

RING finger, H2 subclass, found in Arabidopsis thaliana protein SUGAR INSENSITIVE 3 (SIS3) and similar proteins; SIS3 is an E3 ubiquitin-protein ligase that acts as a positive regulator of sugar signaling during early seedling development. SIS3 contains a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 817193168 346 DNCAICWEKM---DSARKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd23118    1 KTCTICLEDFedgEKLRVLPCQHQFHSECVDQWLRRNPKCPVCR 44

RING-H2 zinc finger domain; There are 8 cysteine/ histidine residues which are proposed to be the conserved residues involved in zinc binding. The protein, of which this domain is the conserved region, participates in diverse functions relevant to chromosome metabolism and cell cycle control.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 817193168  346 DNCAICWEKMDSAR---KLP-----------CGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:pfam12678   1 DTCAICRNPFMEPCpecQAPgddecpvvwgeCGHAFHLHCISRWLKTNNTCPLCR 55

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 817193168 347 NCAICWE----KMDSARKLPCGHLFHNSCLQSWLEQDT-SCPTCR 386
Cdd:cd16478    3 FCGMCGEsigeKNEQLQALPCSHIFHLKCLQTNLRGGTrGCPNCR 47

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 817193168 343 ENSDNCAICWEKMDSARKLPCGHLFHNSCL-QSW-LEQDTSCPTCRQALSMQA 393
Cdd:COG5574  213 LADYKCFLCLEEPEVPSCTPCGHLFCLSCLlISWtKKKYEFCPLCRAKVYPKK 265

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
                 ....*....|....*....|....*....|....*....
gi 817193168 348 CAICWEKMDSARKLPCGHLFHNSCLQSWLEQDT-SCPTC 385
Cdd:cd16449    3 CPICLERLKDPVLLPCGHVFCRECIRRLLESGSiKCPIC 41

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 817193168 348 CAICWEKMDSA---RKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16666    2 CAICLEEYEEGqelRVLPCQHEFHRKCVDPWLLQNHTCPLCL 43

RING finger, H2 subclass, found in Arabidopsis thaliana NEP1-interacting protein-like 1 (NIPL1) and similar proteins; This subfamily includes Arabidopsis thaliana NIPL1 and MISFOLDED PROTEIN SENSING RING E3 LIGASE 1 (MPSR1). NIPL1, also called RING-H2 finger protein ATL27, may be involved in the early steps of the plant defense signaling pathway. MPSR1 is a cytoplasmic E3 ubiquitin-protein ligase involved in protein quality control (PQC) under proteotoxic stress. It is essential for plant survival under proteotoxic stress. It functions by removing damaged proteins before they form cytotoxic aggregates. It recognizes misfolded proteins selectively and tethers polyubiquitin chains to the proteins directly for subsequent degradation by the 26S proteasome pathway. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 817193168 348 CAIC---WEKMDSARKLP-CGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd23119    2 CTIClqdLQVGEIARSLPhCHHTFHLGCVDKWLGRHGSCPVCR 44

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 817193168 346 DNCAICWEKMDSA---RKLPCGHLFHNSCLQSWLEQDTSCPTCR 386
Cdd:cd16670    1 ESCAVCLDQFYKNqclRVLPCLHEFHRDCVDPWLLLQQTCPLCK 44

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-c and similar proteins; Cbl-c, also known as RING finger protein 57 (RNF57), SH3-binding protein Cbl-3, SH3-binding protein Cbl-c, or signal transduction protein Cbl-c, is an E3 ubiquitin-protein ligase expressed exclusively in epithelial cells. It contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a C3HC4-type RING-HC finger, and a short proline-rich region, but lacks the ubiquitin-associated (UBA) leucine zipper motif that are present in Cbl and Cbl-b. Cbl-c acts as a regulator of epidermal growth factor receptor (EGFR)-mediated signal transduction. It also suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Moreover, Cbl-c ubiquitinates and downregulates RETMEN2A and implicates Enigma (PDLIM7) as a positive regulator of RETMEN2A by blocking Cbl-mediated ubiquitination and degradation. The ubiquitin ligase activity of Cbl-c is increased via the interaction of its RING-HC finger domain with a LIM domain of the paxillin homolog, hydrogen peroxide induced construct 5 (Hic-5).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 817193168 348 CAICWEKMDSARKLPCGHLFHNSCLQSWLEQDT-SCPTCR 386
Cdd:cd16710   16 CKICAERDKDVRIEPCGHLLCSCCLAAWQHSDSqTCPFCR 55

RING finger, H2 subclass, found in anaphase-promoting complex subunit 11 (APC11) and similar proteins; APC11, also known as cyclosome subunit 11, or hepatocellular carcinoma-associated RING finger protein, is a C3H2C3-type RING-H2 protein that facilitates ubiquitin chain formation by recruiting ubiquitin-charged ubiquitin conjugating enzymes (E2) through its RING-H2 domain. APC11 and its partner, the cullin-like subunit APC2, form the dynamic catalytic core of the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), also known as the cyclosome, which is a ubiquitin-protein ligase (E3) composed of at least 12 subunits and controls cell division by ubiquitinating cell cycle regulators, such as cyclin B and securin, to drive their timely degradation. APC11 can be inhibited by hydrogen peroxide, which may contribute to the delay in cell cycle progression through mitosis that is characteristic of cells subjected to oxidative stress. APC11 contains a canonical RING-H2-finger that coordinate two Zn2+ ions. In addition, it contains a third Zn2+-binding site that is not essential for its ligase activity.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 817193168 345 SDNCAICWEKMDSA---RKLP----------CGHLFHNSCLQSWLEQDTS---CPTCRQA 388
Cdd:cd16456    1 DDVCGICRMAFDGCcpdCKFPgddcplvwgkCSHCFHMHCILKWLNSQQVqqhCPMCRQE 60

CUE domain; CUE domains have been shown to bind ubiquitin. It has been suggested that CUE domains are related to pfam00627 and this has been confirmed by the structure of the domain. CUE domains also occur in two protein of the IL-1 signal transduction pathway, tollip and TAB2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 817193168  456 DAMARQVQQLFPHYPRNIVLEDLR-VTRSVELTIENILDGR 495
Cdd:pfam02845   2 EQMLETLKEMFPDLDEEVIRAVLEaSNGNVEAAINALLEGS 42

RING finger, H2 subclass, found in Arabidopsis thaliana RING-H2 zinc finger protein RHF2A and similar proteins; RHF2A is an E3 ubiquitin-protein ligase involved in the positive regulation of the gametogenesis progression. It is required for the degradation of KRP6, a cyclin-dependent kinase inhibitor which accumulates during meiosis and blocks the progression of subsequent mitoses during gametophytes development. It functions in association with RHF1A. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

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gi 817193168 346 DNCAICWEKM---DSARKLPCGHLFHNSCLQSWLEQDTSCPTCRQALSMQ 392
Cdd:cd23122   12 DACSICLESFceaDPATVTSCKHEYHLQCILEWSQRSKECPMCWQALSLK 61