SPRY domain at N-terminus of Really Interesting New Gene (RING) finger domain; This SPRY domain is found at the N-terminus of RING finger domains which are present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RING-finger domain is a type of Zn-finger that binds two Zn atoms and is identified in proteins with a wide range of functions such as viral replication, signal transduction, and development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 410 GVWYYEVTVITSGVMQIGWATRDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHSHPCWKEGDTIGFLLDLHEKQ 489
Cdd:cd12883     1 GVWYYEVTVLTSGVMQIGWATKDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNAKSKPHTHPRWKPGDVLGCLLDLNKKQ 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1729002139 490 MIFYLNGNQLPAEKQVFSSAISGFFAAASFMSYQQCEFNFG 530
Cdd:cd12883    81 MIFSLNGNRLPPERQVFTSAKSGFFAAASFMSFQQCEFNFG 121

SPRY domain at N-terminus of Really Interesting New Gene (RING) finger domain; This SPRY domain is found at the N-terminus of RING finger domains which are present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RING-finger domain is a type of Zn-finger that binds two Zn atoms and is identified in proteins with a wide range of functions such as viral replication, signal transduction, and development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 410 GVWYYEVTVITSGVMQIGWATRDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHSHPCWKEGDTIGFLLDLHEKQ 489
Cdd:cd12883     1 GVWYYEVTVLTSGVMQIGWATKDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNAKSKPHTHPRWKPGDVLGCLLDLNKKQ 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1729002139 490 MIFYLNGNQLPAEKQVFSSAISGFFAAASFMSYQQCEFNFG 530
Cdd:cd12883    81 MIFSLNGNRLPPERQVFTSAKSGFFAAASFMSFQQCEFNFG 121

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 411 VWYYEVTV--ITSGVMQIGWATRDSKFLNHEGygIGDDEYSCAYDGCRQLIWYNARSKPHSHPCWKEGDTIGFLLDLHEK 488
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1729002139 489 QMIFYLNGNQLPAEKQVFSSAiSGFFAAASFMSYQQCEFNFG 530
Cdd:pfam00622  79 TISFTKNGKSLGYAFRDVPFA-GPLFPAVSLGAGEGLKFNFG 119

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1729002139 574 RENCCTLCCDEVADTELRPCGHSDLCMECALQLE----TCPLCRQEIQTR 619
Cdd:pfam13920   1 EDLLCVICLDRPRNVVLLPCGHLCLCEECAERLLrkkkKCPICRQPIESV 50

SPRY domain at N-terminus of Really Interesting New Gene (RING) finger domain; This SPRY domain is found at the N-terminus of RING finger domains which are present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RING-finger domain is a type of Zn-finger that binds two Zn atoms and is identified in proteins with a wide range of functions such as viral replication, signal transduction, and development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 410 GVWYYEVTVITSGVMQIGWATRDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHSHPCWKEGDTIGFLLDLHEKQ 489
Cdd:cd12883     1 GVWYYEVTVLTSGVMQIGWATKDSKFLNHEGYGIGDDEYSCAYDGCRQLIWYNAKSKPHTHPRWKPGDVLGCLLDLNKKQ 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1729002139 490 MIFYLNGNQLPAEKQVFSSAISGFFAAASFMSYQQCEFNFG 530
Cdd:cd12883    81 MIFSLNGNRLPPERQVFTSAKSGFFAAASFMSFQQCEFNFG 121

SPRY domain; SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L). B30.2 also contains residues in the N-terminus that form a distinct PRY domain structure; i.e. B30.2 domain consists of PRY and SPRY subdomains. B30.2 domains comprise the C-terminus of three protein families: BTNs (receptor glycoproteins of immunoglobulin superfamily); several TRIM proteins (composed of RING/B-box/coiled-coil or RBCC core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). TRIM/RBCC proteins are involved in a variety of processes, including apoptosis, cell cycle regulation, cell growth, senescence, viral response, meiosis, cell differentiation, and vesicular transport. Genes belonging to this family are implicated in several human diseases that vary from cancer to rare genetic syndromes. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site. While SPRY domains are evolutionarily ancient, B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. Mutations found in the SPRY-containing proteins have shown to cause Mediterranean fever and Opitz syndrome.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 410 GVWYYEVTVIT--SGVMQIGWATRDSKFLNHEGYGigDDEYSCAYDGCRQLIWYNARSKPHSHPcWKEGDTIGFLLDLHE 487
Cdd:cd11709     1 GKWYWEVRVDSgnGGLIQVGWATKSFSLDGEGGVG--DDEESWGYDGSRLRKGHGGSSGPGGRP-WKSGDVVGCLLDLDE 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1729002139 488 KQMIFYLNGNQLPAEKQVFSSAISGFFAAASFMSYQQCEFN 528
Cdd:cd11709    78 GTLSFSLNGKDLGVAFTNLFLKGGGLYPAVSLGSGQGVTIN 118

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 411 VWYYEVTV--ITSGVMQIGWATRDSKFLNHEGygIGDDEYSCAYDGCRQLIWYNARSKPHSHPCWKEGDTIGFLLDLHEK 488
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1729002139 489 QMIFYLNGNQLPAEKQVFSSAiSGFFAAASFMSYQQCEFNFG 530
Cdd:pfam00622  79 TISFTKNGKSLGYAFRDVPFA-GPLFPAVSLGAGEGLKFNFG 119

SPRY domain 2 (SPRY2) of ryanodine receptor (RyR); This SPRY domain (SPRY2) is the second of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, The SPRY2 domain has been shown to bind to the dihydropryidine receptor (DHPR) II-III loop and the ASI region of RyR1

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 404 TFCVDSGVWYYEVTVITSGVMQIGWATRDSkflnHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHSHpcWKEGDTIGFLL 483
Cdd:cd12878     8 TYAVTSGKWYFEFEVLTSGYMRVGWARPGF----RPDLELGSDDLSYAFDGFLARKWHQGSESFGKQ--WQPGDVVGCML 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1729002139 484 DLHEKQMIFYLNGnQLPAEKQVFSSAIS------GFFAAASFMSYQQCEFNFG 530
Cdd:cd12878    82 DLVDRTISFTLNG-ELLIDSSGSEVAFKdieigeGFVPACSLGVGQKGRLNLG 133

SPRY domain associated with DEAD box gene DDX1; This SPRY domain is associated with the DEAD box gene, DDX1, an RNA-dependent ATPase involved in HIV-1 Rev function and virus replication. It is suggested that DDX1 acts as a cellular cofactor by promoting oligomerization of Rev on the Rev response element (RRE). DDX1 RNA is overexpressed in breast cancer, data showing a strong and independent association between poor prognosis and deregulation of the DEAD box protein DDX1, thus potentially serving as an effective prognostic biomarker for early recurrence in primary breast cancer. DDX1 also interacts with RelA and enhances nuclear factor kappaB-mediated transcription. DEAD-box proteins are associated with all levels of RNA metabolism and function, and have been implicated in translation initiation, transcription, RNA splicing, ribosome assembly, RNA transport, and RNA decay.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 373 LNSNDVSEYLKISPHGLEARC-DASSFESVRCTFCV-DSGVWYYEVTVITSGVMQIGWATRDSKFlnhegyGIGDDEYSC 450
Cdd:cd12873     1 MNPYDRDAALAISPDGLLCQSrEEKGWQGCRATKGVkGKGKYYYEVTVTDEGLCRVGWSTEDASL------DLGTDKFGF 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 451 AYDG------CRQLIWYnarSKPHSHpcwkeGDTIGFLLDLHEKQMIFYLNGNQLP-AEKQVFSSAISGFFAAASfMSYQ 523
Cdd:cd12873    75 GYGGtgkkshGRQFDDY---GEPFGL-----GDVIGCYLDLDNGTISFSKNGKDLGkAFDIPPHLRNSALFPAVC-LKNA 145

                         170
                  ....*....|
gi 1729002139 524 QCEFNFGAKP 533
Cdd:cd12873   146 EVEFNFGDKP 155

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1729002139 574 RENCCTLCCDEVADTELRPCGHSDLCMECALQLE----TCPLCRQEIQTR 619
Cdd:pfam13920   1 EDLLCVICLDRPRNVVLLPCGHLCLCEECAERLLrkkkKCPICRQPIESV 50

SPRY domain in Ran binding proteins, SSH4, HECT E3 and SPRYD3; This family includes SPRY domains found in Ran binding proteins (RBP or RanBPM) 9 and 10, SSH4 (suppressor of SHR3 null mutation protein 4), SPRY domain-containing protein 3 (SPRYD3) as well as HECT, a C-terminal catalytic domain of a subclass of ubiquitin-protein ligase (E3). RanBP9 and RanBP10 act as androgen receptor (AR) coactivators. Both consist of the N-terminal proline- and glutamine-rich regions, the SPRY domain, and LisH-CTLH and CRA motifs. The SPRY domain in SSH4 may be involved in cargo recognition, either directly or by combination with other adaptors, possibly leading to a higher selectivity. SPRYD3 is highly expressed in most tissues in humans, possibly involved in important cellular processes. HECT E3 mediates the direct transfer of ubiquitin from E2 to substrate.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 407 VDSGVWYYEVTVI---TSGVMQIGWATRDSKFLNHegygIGDDEYSCAY---DGcrQLIWYNARSKPHSHPcWKEGDTIG 480
Cdd:cd12885    11 PKVPVFYFEVTILdlgEKGIVSIGFCTSGFPLNRM----PGWEDGSYGYhgdDG--RVYLGGGEGENYGPP-FGTGDVVG 83

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1729002139 481 FLLDLHEKQMIFYLNGNQL-PAEKQVFSsaiSGFFAAASFmSYQQCEF--NFG 530
Cdd:cd12885    84 CGINFKTGEVFFTKNGELLgTAFENVVK---GRLYPTVGL-GSPGVKVrvNFG 132

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein CARP-1, CARP-2 and similar proteins; The CARP subfamily includes CARP-1 and CARP-2 proteins, both of which are E3 ubiquitin ligases that ubiquitinate apical caspases and target them for proteasome-mediated degradation. As a novel group of caspase regulators with a FYVE-type zinc finger domain, they do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8, and caspase 10. Moreover, they stabilize MDM2 by inhibiting MDM2 self-ubiquitination, as well as by targeting 14-3-3sigma for degradation. They work together with MDM2 to enhance p53 degradation, thereby inhibiting p53-mediated cell death. CARPs contain an N-terminal FYVE-like domain that can serve as a membrane-targeting or endosome localizing signal and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1729002139 576 NCCTLCCDEVADTELRPCGHSDLCMECALQLETCPLCRQEIQTRVR 621
Cdd:cd16500     1 DLCKICMDAAIDCVLLECGHMVTCTDCGKKLSECPICRQYVVRVVH 46

RING finger, HC subclass, found in leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) and similar proteins; LRSAM1, also known as Tsg101-associated ligase (TAL), or RIFLE, is an E3 ubiquitin-protein ligase that physically associates with, and selectively ubiquitylates, Tsg101, an E2-like molecule that regulates vesicular trafficking processes in yeast and mammals. It regulates a Tsg101-associated complex responsible for the sorting of cargo into cytoplasm-containing vesicles that bud at the multivesicular body and at the plasma membrane. LRSAM1 is a multidomain protein containing an N-terminal leucine-rich repeat (LRR), followed by several recognizable motifs, including an ezrin-radixin-moezin (ERM) domain, a coiled-coil (CC) region, a SAM domain, and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQLETCPLCRQEIQTRVR 621
Cdd:cd16515     4 CVVCMDAESQVIFLPCGHVCCCQTCSSSLSTCPLCRADITQRVR 47

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1729002139 575 ENCCTLCCDEVADTELRPCGHSDLCMECALQLETCPLCRQEIQTRVR 621
Cdd:cd16713     7 ERTCKVCMDKEVSIVFIPCGHLVVCTECAPSLRKCPICRATIKGTVR 53

SPRY domain-like in bacteria; This family contains SPRY-like domains that are found only in bacterial and are mostly uncharacterized. SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 eukaryotic protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729002139 410 GVWYYEVTVITSGV---MQIGWA----TRDSKFLNHEGYGIGDDEYScaYDGcrqLIWYNARSKPHSHPCWKEGDTIGFL 482
Cdd:cd12886     1 GKWYWEVTVVSSAAstyAGIGVAnaaaTGNNGLNGIELSSIGYSLGV--YSG---NKLSNGSSVATYGAGFTAGDVIGVA 75

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1729002139 483 LDLHEKQMIFYLNG------NQLPAEKQVFSSaiSGFFAAASFMSYQQCEF--NFG 530
Cdd:cd12886    76 LDLDAGKIWFYKNGvwqgggDPAPGTNPAFAG--TAMYPAVTGGSSTGGSFtaNFG 129

RING finger, HC subclass, found in neuralized-like protein 3 (NEURL3) and similar proteins; NEURL3, also known as lung-inducible neuralized-related C3HC4 RING domain protein (LINCR), is a novel inflammation-induced E3 ubiquitin-protein ligase encoded by LINCR, a glucocorticoid-attenuated response gene induced in the lung during endotoxemia. It is expressed in alveolar epithelial type II cells, preferentially interacts with the ubiquitin-conjugating enzyme UbcH6, and generates polyubiquitin chains linked via non-canonical lysine residues. Overexpression of NEURL3 in the developing lung epithelium inhibits distal differentiation and induces cystic changes in the Notch signaling pathway. NEURL3 contains an N-terminal neuralized homology repeat (NHR) domain similar to the SPRY (SPla and the RYanodine receptor) domain and a C-terminal C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQL----ETCPLCRQEIQ 617
Cdd:cd16552     4 CAICFHHTANTRLVPCGHSHFCGSCAWHIfrdtARCPVCRWQIE 47

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 1 (CARP1) and similar proteins; CARP1, also known as caspase regulator CARP1, FYVE-RING finger protein Momo, RING finger homologous to inhibitor of apoptosis protein (RFI), RING finger protein 34 (RNF34), or RING finger protein RIFF, is a nuclear protein that functions as a specific E3 ubiquitin ligase for the transcriptional coactivator PGC-1alpha, a master regulator of energy metabolism and adaptive thermogenesis in the brown fat cell which negatively regulates brown fat cell metabolism. It is preferentially expressed in esophageal, gastric, and colorectal cancers, suggesting a possible association with the development of digestive tract cancers. It regulates the p53 signaling pathway by degrading 14-3-3 sigma and stabilizing MDM2. CARP1 does not localize to membranes in the cell and is involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10. CARP1 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1729002139 575 ENCCTLCCDEVADTELRPCGHSDLCMECALQLETCPLCRQEI 616
Cdd:cd16706     4 DNLCRICMDAVIDCVLLECGHMVTCTKCGKRMSECPICRQYV 45

RING finger, HC subclass, found in mind bomb MIB1, MIB2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the first RING-HC finger of MIB1 and MIB2, as well as the second RING-HC finger of MIB1.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQLETCPLCR 613
Cdd:cd16519     3 CRVCSDKKALVLFQPCGHVVACEECSLRMKKCLQCK 38

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 2 (CARP-2) and similar proteins; CARP-2, also known as rififylin, caspase regulator CARP2, FYVE-RING finger protein Sakura (Fring), RING finger and FYVE-like domain-containing protein 1, RING finger protein 189 (RNF189), or RING finger protein 34-like, is an endosome-associated E3 ubiquitin-protein ligase that targets internalized receptor interacting kinase (RIP) for proteasome-mediated degradation. It acts as a negative regulator of tumor necrosis factor (TNF)-induced nuclear factor (NF)-kappaB activation. It also regulates the p53 signaling pathway by degrading 14-3-3sigma and stabilizing MDM2. As a caspase regulator, CARP2 does not localize to membranes in the cell and is involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10. CARP2 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1729002139 575 ENCCTLCCDEVADTELRPCGHSDLCMECALQLETCPLCRQ 614
Cdd:cd16707     2 ENLCKICMDSPIDCVLLECGHMVTCTKCGKRMSECPICRQ 41

RING finger, HC subclass, found in zinc finger protein 598 (ZNF598) and similar proteins; ZNF598 associates with eukaryotic initiation factor 4E (eIF4E) homologous protein from mammals (m4EHP) by binding to Grb10-interacting GYF protein 2 (GIGYF2). The m4EHP-GIGYF2 complex functions as a translational repressor and is essential for normal embryonic development of mammalian. ZNF598 harbors a C3HC4-type RING-HC finger at its N-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1729002139 576 NCCTLCCDEVADTELRPCGHSdLCMECALQLET------CPLCRQEIQ 617
Cdd:cd16615     1 ETCVICCEEIEYFAVGPCNHP-VCYKCSLRMRVlykdkyCPICRTELD 47

RING finger, HC subclass, found in RNA-binding proteins of the evolutionarily-conserved MEX-3 family; MEX-3 phosphoproteins are found in vertebrates. They are mediators of post-transcriptional regulation in different organisms, and have been implicated in many core biological processes, including embryonic development, epithelial homeostasis, immune responses, metabolism, and cancer. They contain two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. They shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. The RNA-binding protein MEX-3 from nematode Caenorhabditis elegans is the founding member of the MEX-3 family. Due to the lack of a RING-HC finger, it is not included here.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQL-----ETCPLCRQ 614
Cdd:cd16518     3 CVVCFESEVVAALVPCGHNLFCMECANRIceksdPECPVCHT 44

RING finger, HC subclass, found in RNA-binding protein MEX3C; MEX3C, also known as RING finger and KH domain-containing protein 2 (RKHD2), or RING finger protein 194 (RNF194), is an RNA-binding phosphoprotein that acts as a suppressor of chromosomal instability. It functions as an ubiquitin E3 ligase responsible for the post-transcriptional, HLA-A allotype-specific regulation of MHC class I molecules (MHC-I). It also modifies retinoic acid inducible gene-1 (RIG-I) in stress granules and plays a critical role in eliciting antiviral immune responses. Moreover, MEX3C plays an essential role in normal postnatal growth via enhancing the local expression of insulin-like growth factor 1 (IGF1) in bone. It may also be involved in metabolic regulation of energy balance. MEX3C contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3C shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQ-----LETCPLCrqeiQTRVRQISHI 626
Cdd:cd16722     4 CVICFENEVIAALVPCGHNLFCMECANKicekeTPSCPVC----QTAVTQAIQI 53

SPRY domain in the suppressor of cytokine signaling 3 (SOCS3) family; The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor, but SOCS3 regulates cellular response to a variety of cytokines such as leukemia inhibitory factor (LIF) and interleukin 6. SOCS3, along with SOCS1, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS. In non-small cell lung cancer (NSCLC), SOCS3 is silenced and proline-rich tyrosine kinase 2 (Pyk2) is over-expressed; it has been suggested that SOCS3 could be an effective way to prevent the progression of NSCLC due to its role in regulating Pyk2 expression.

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gi 1729002139 410 GVWYYEVTVI-----TSgvMQIGWATRDSKfLNHEGY----GIGDDEYSC--AYDGcrqLIWYNARSKPHSHPCWKEGDT 478
Cdd:cd12876    44 GQHYWEIKMSspvygTD--MMVGVGTKKAD-LHAYRYefcsLLGEDEESWglSYKG---LLWHDGQSRPYTSPFGNQGTI 117

                          90
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gi 1729002139 479 IGFLLDLHEKQMIFYLNG 496
Cdd:cd12876   118 IGVHLDMWRGTLTFYKNG 135

SPRY domain-containing protein 7; This family contains SPRY domain-containing protein 7 (also known as SPRY domain-containing protein 7 or CLL deletion region gene 6 protein homolog or CLLD6 or chronic lymphocytic leukemia deletion region gene 6 protein homolog). In humans, CLLD6 is highly expressed in heart, skeletal muscle, and testis as well as cancer cell lines. It also has cross-species conservation, suggesting that it is likely to carry out important cellular processes.

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gi 1729002139 413 YYEVTVITSGVMQIGWATRDSKfLNHEGYGIgdDEYSCA--YDGCrqlIWYN--ARSKPHSHPCwkEGDTIGFLLDlHeK 488
Cdd:cd12880    32 YFEVKIQSTGVWGVGLATRKTD-LNRVPLGN--DAESWVlrSDGT---IWHNgeVIHKLKQLVE--EGDVIGVTYD-H-V 101

                          90
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gi 1729002139 489 QMIFYLNGNQLP 500
Cdd:cd12880   102 ELNFYLNGKPLD 113

Modified RING finger, HC subclass (C3HC5-type), found in cell growth regulator with RING finger domain protein 1 (CGRRF1) and similar proteins; CGRRF1, also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. CGRRF1 contains a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQLETCPLCR 613
Cdd:cd16787     3 CVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 38

first RING finger, HC subclass, found in mind bomb 1 (MIB1) and similar proteins; MIB1, also known as DAPK-interacting protein 1 (DIP-1) or zinc finger ZZ type with ankyrin repeat domain protein 2, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands, and thus plays an essential role in controlling metazoan development by Notch signaling. It is also involved in Wnt/beta-catenin signaling and nuclear factor (NF)-kappaB signaling, and has been implicated in innate immunity, neuronal function, genomic stability, and cell death. MIB1 contains an MZM region with two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region consisting of three C3HC4-type RING-HC fingers. This model corresponds to the first RING-HC finger.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQLETCPLCR 613
Cdd:cd16724     3 CMVCSDMKRDTLFGPCGHIATCSLCSPRVKKCLICK 38

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM9, TRIM67, and similar proteins; Tripartite motif-containing proteins TRIM9 and TRIM67 belong to the C-I subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, consisting of three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, a fibronectin type III (FN3) domain, and a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. TRIM9 (the human ortholog of rat Spring), also known as RING finger protein 91 (RNF91), is a brain-specific E3 ubiquitin-protein ligase collaborating with an E2 ubiquitin conjugating enzyme UBCH5b. TRIM9 plays an important role in the regulation of neuronal functions and participates in neurodegenerative disorders through its ligase activity. TRIM67, also known as TRIM9-like protein (TNL), is a protein selectively expressed in the cerebellum. It interacts with PRG-1, an important molecule in the control of hippocampal excitability dependent on presynaptic LPA2 receptor signaling, and 80K-H, also known as glucosidase II beta, a protein kinase C substrate.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSdLCMECALQLE-TCPLCRQ 614
Cdd:cd16576     6 CPVCGSLFTEPVILPCSHN-LCLGCALNIQlTCPICHK 42

Modified RING finger, HC subclass (C3HC5-type), found in RING finger proteins, RNF26, RNF197 (CGRRF1), RNF156 (MGRN1), RNF157 and similar proteins; This subfamily corresponds to a group of RING finger proteins containing a modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain. Cell growth regulator with RING finger domain protein 1 (CGRRF1), also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction. Mahogunin ring finger-1 (MGRN1), also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase MGRN1. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQL--ETCPLCR 613
Cdd:cd16649     3 CVVCLENPASVLLLPCRHLCLCEVCAKGLrgKTCPICR 40

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.

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gi 1729002139 578 CTLCCDEVADTELRPCGHS---DLCMECALQLETCPLCRQEIQ 617
Cdd:cd16527     3 CSLCLEERRHPTATPCGHLfcwSCITEWCNEKPECPLCREPFQ 45

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).

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gi 1729002139 578 CTLCCDEVADTELRPCGHsdLCMECALQL------ETCPLCRQEIQTR 619
Cdd:cd16710    16 CKICAERDKDVRIEPCGH--LLCSCCLAAwqhsdsQTCPFCRCEIKGR 61

Prokaryotic RING finger family 4; RING finger family domain found sporadically in bacteria. The finger is fused to an N-terminal alpha-helical domain, ROT/Trove-like repeats and a C-terminal TerD domain. The architecture suggests a possible role in an RNA-processing complex.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSdLCMEC--ALQLETCPLCRQEI 616
Cdd:pfam14447   1 CVLCGRNGTVHALIPCGHL-VCRDCfdGSDFSACPICRRRI 40

RING finger, HC subclass, found in mind bomb MIB1, MIB2, RGLG1, RGLG2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the third RING-HC finger of MIB1, as well as the second RING-HC finger of MIB2. In addition to MIB1 and MIB2, the RING-HC fingers of RING domain ligase RGLG1, RGLG2 and similar proteins from plant are also included in this model. RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. All RGLG proteins contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

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gi 1729002139 577 CCTLCCDEVADTELRpCGHSdLCMECALQLETCPLCRQEI 616
Cdd:cd16520     2 LCPICMERKKNVVFL-CGHG-TCQKCAEKLKKCPICRKPI 39

RING finger, HC subclass, found in tripartite motif-containing protein 69 (TRIM69) and similar proteins; TRIM69, also known as RFP-like domain-containing protein trimless or RING finger protein 36 (RNF36), is a testis E3 ubiquitin-protein ligase that plays a specific role in apoptosis and may also play an important role in germ cell homeostasis during spermatogenesis. TRIM69 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

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gi 1729002139 575 ENCCTLCCDEVADTELRPCGHsDLCMECALQL-------ETCPLCRQEIQTR 619
Cdd:cd16611     4 ELHCPLCLDFFRDPVMLSCGH-NFCQSCITGFwelqaedTTCPECRELCQYR 54

Modified RING finger, HC subclass (C4C4-type), found in Saccharomyces cerevisiae amino acid sensor-independent protein Asi1p, Asi3p and similar proteins; Asi1p and Asi3p are inner nuclear membrane proteins that act as negative regulators of SPS (Ssy1-Ptr3-Ssy5)-sensor signaling in yeast. Together with Asi2p, they assemble into an Asi complex that functions in the SPS amino acid sensing pathway involved in degradation of Stp1 and Stp2 transcription factors. Both Asi1p and Asi3p contain five membrane-spanning domains, as well as highly conserved RING fingers at their extreme C termini, which are C4C4-type RING finger motifs whose overall folding is similar to that of the C3HC4-type RING-HC finger.

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gi 1729002139 578 CTLCCDEVADTELRPCGHSDLCMECALQL-----ETCPLCRQEI 616
Cdd:cd16616     4 CVICKSNPRNIVLWPCRCLALCDDCRLSLamrgfHTCVCCRREV 47