RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462553801   7 EEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRC---GKACPECREPFPDGAELR 61
Cdd:cd16609     1 EEELTCSICLGLYQDPVTLPCQHSFCRACIEDHWRQKdegSFSCPECRAPFPEGPTLE 58

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462553801   7 EEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRC---GKACPECREPFPDGAELR 61
Cdd:cd16609     1 EEELTCSICLGLYQDPVTLPCQHSFCRACIEDHWRQKdegSFSCPECRAPFPEGPTLE 58

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801  439 GHHYWEVRASD-HSVTLGVSYPQLPRcrlgPHTDNIGRGPCSWGLCVqeDSLQAWHNGEAQRLP---GVSGRLLGMDLDL 514
Cdd:smart00449   2 GRHYFEVEIGDgGHWRVGVATKSVPR----GYFALLGEDKGSWGYDG--DGGKKYHNSTGPEYGlplQEPGDVIGCFLDL 75

                           90       100       110
                   ....*....|....*....|....*....|....
gi 2462553801  515 ASGCLTFYSLEPQTQPLYTFHALFNQPLTPVFWL 548
Cdd:smart00449  76 EAGTISFYKNGKYLHGLAFFDVKFSGPLYPAFSL 109

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462553801   6 LEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKaCPECREPFPDgAELRRNVALSGVLE 71
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPK-CPLCRAEDQE-SKLRSNWLVSEIVE 86

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 2462553801 441 HYWEVR---ASDHSVTLGVSYPQLPRcrlgphTDNIGRGPCSWGLCVQEDSLQAWHN--GEAQRLPG-VSGRLLGMDLDL 514
Cdd:pfam00622   2 HYFEVEifgQDGGGWRVGWATKSVPR------KGERFLGDESGSWGYDGWTGKKYWAstSPLTGLPLfEPGDVIGCFLDY 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2462553801 515 ASGCLTFYSLEpqTQPLYTFHAL-FNQPLTPVFWLLEGRTLTLC 557
Cdd:pfam00622  76 EAGTISFTKNG--KSLGYAFRDVpFAGPLFPAVSLGAGEGLKFN 117

B-box zinc finger;

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 2462553801  94 RCPRHGR-PLELFCRTEGRCVCSVCTVRECRLHERALL 130
Cdd:pfam00643   5 LCPEHEEePLTLYCNDCQELLCEECSVGEHRGHTVVPL 42

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 2462553801   92 AARCPRHG-RPLELFCRTEGRCVCSVCTVRECRLHERALL 130
Cdd:smart00336   3 APKCDSHGdEPAEFFCEECGALLCRTCDEAEHRGHTVVLL 42

PRY/SPRY domain, also known as B30.2; This domain contains residues in the N-terminus that form a distinct PRY domain structure such that the 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 core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). 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. Among the TRIM proteins, also known as the N-terminal RING finger/B-box/coiled coil (RBCC) family, only Classes I and II contain the B30.2 domain that has evolved under positive selection. Class I TRIM proteins include multiple members involved in antiviral immunity at various levels of interferon signaling cascade. Among the 75 human TRIMs, roughly half enhance immune response, which they do at multiple levels in signaling pathways. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 390 LTFDPVSANRHFYLSRQDQQVKHCRQSRGP--GGPGSFELWQVQCAQSFQAGHHYWEVRASD-HSVTLGVSYPQLPRCRL 466
Cdd:cd12874     1 LTFDPDTAHLNLILSDDLRSVRVGDISQHPpePPPRFFECWQVLGSQSFSSGRHYWEVDVQDdSSWYVGVTYKSLPRKGK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 467 gphTDNIGRGPCSWGLCVQEDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLEPQTQPLYTFHALFNQPLTPVF 546
Cdd:cd12874    81 ---MSNLGRNNGSWCLEWRENEFSAWHNNPETRLPVTPPRRLGVFLDCDGGSLSFYGVTDGVQLLYTFKAKFTEPLYPAF 157

                         170
                  ....*....|.
gi 2462553801 547 WLLEGRTLTLC 557
Cdd:cd12874   158 WLGEGSTLSIC 168

Stonustoxin subunit alpha or SNTX subunit alpha; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of Stonustoxin alpha proteins. Stonustoxin (SNTX) is a multifunctional lethal protein isolated from venom elaborated by the stonefish. It comprises two subunits, termed alpha and beta. SNTX elicits an array of biological responses, particularly a potent hypotension and respiratory difficulties.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 380 RRKLWQNYRNLTFDPVSANRHFYLSRQDQQVKHCRQSRG-PGGPGSFELW-QVQCAQSFqAGHHYWEVRASDHSVTLGVS 457
Cdd:cd16040     1 REEFLKYACQLTLDPNTAHRNLSLSEGNRKVTRVKEEQPyPDHPERFDYWpQVLCREGL-SGRCYWEVEWSGGGVDIAVA 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 458 YPQLPR------CRLGpHTDNigrgpcSWGLCVQEDSLQAWHNGEAQR--LPGVSGRLLGMDLDLASGCLTFYSLEPQTQ 529
Cdd:cd16040    80 YKGISRkgdgddSRFG-YNDK------SWSLECSPSGYSFWHNNKKTEisVPSSSSSRVGVYLDHSAGTLSFYSVSDTMT 152

                         170       180
                  ....*....|....*....|....*...
gi 2462553801 530 PLYTFHALFNQPLTPVFWLLEGRTLTLC 557
Cdd:cd16040   153 LLHTVQTTFTEPLYPGFGVGYGSSVKLC 180

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462553801   6 LEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGK---ACPECREPFPDGAELRRNVALSGVLE 71
Cdd:cd16597     2 LEEELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQHGseySCPQCRATFPRRPELHKNTVLRNIVE 70

PRY/SPRY domain in RING finger protein RNF135; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of the RING finger protein RNF135 (also known as Riplet/RNF135), which ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Normally, RIG-I is activated by TRIM25 in response to viral infection, leading to activation of the RIG-I signaling pathway, thus resulting in type I interferon production to limit viral replication. However, RNF135, consisting of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs and showing sequence similarity to TRIM25, acts as an alternative factor that promotes RIG-I activation independent of TRIM25.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 390 LTFDPVSANRHFYLSRQDQQVKHCR-QSRGPGGPGSFELWQVQCAQSFQAGHHYWEVRASDHSV-TLGVSYPQLPRcrlg 467
Cdd:cd12902     1 PTFDLRSLSCSLEVSEDSRKVTVSHgPQAYAWSPDRFSISQVLCSQAFSSGQHYWEVDTRQCSHwAVGVASWEMSR---- 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 468 phTDNIGRGPCSWglCVQ---EDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLEPQTQPLYTFHALFNQPLTP 544
Cdd:cd12902    77 --DQMLGRTMDSW--CIEwkgTGQLSAWHMNKETVLGSDKPRVVGIWLDLEEGKLAFYSVANQERLLHECEVSASSPLHP 152

                  ....
gi 2462553801 545 VFWL 548
Cdd:cd12902   153 AFWL 156

B-box-type 2 zinc finger found in tripartite motif-containing protein 65 (TRIM65) and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5 enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 belongs to the C-IV subclass of 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 RING finger, 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. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2462553801  93 ARCPRHGRPLELFCRTEGRCVCSVCTVRECRLHERALLDAER 134
Cdd:cd19835     1 TLCQRHGRPLELYCRTEKRCVCCKCTVKECRNHNRVLLEEER 42

PRY/SPRY domain in tripartite motif-containing domain 25 (TRIM25); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM25 proteins (composed of RING/B-box/coiled-coil core and also known as RBCC proteins). TRIM25 (also called Efp) ubiquitinates the N terminus of the viral RNA receptor retinoic acid-inducible gene-I (RIG-I) in response to viral infection, leading to activation of the RIG-I signaling pathway, thus resulting in type I interferon production to limit viral replication. It has been shown that the influenza A virus targets TRIM25 and disables its antiviral function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 429 QVQCAQSFQAGHHYWEVRASDHSVT-LGVSYPQLPRcrLGPHTdNIGRGPCSWglCVQ--EDSLQAWHNGEAQRLPGVSG 505
Cdd:cd13736    42 QVLGLHCFKQGIHYWEVELQKNNFCgVGICYGSMDR--QGPES-RLGRNSESW--CVEwfNVKISAWHNNVEKTLPSTKA 116

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462553801 506 RLLGMDLDLASGCLTFYSLEPQTQPLYTFHALFNQPLTPVFWLLE-GRTLTLC 557
Cdd:cd13736   117 TRVGVLLNCDHGFVIFFAVQDKVHLMYKFKVDFTEALYPAFWVFSaGTTLSLC 169

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, closely related tripartite motif-containing proteins, belong 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462553801   6 LEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGK--ACPECREPFPD 56
Cdd:cd16594     2 LQEELTCPICLDYFTDPVTLDCGHSFCRACIARCWEEPETsaSCPQCRETCPQ 54

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2462553801   6 LEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGK--ACPECREPFPDG 57
Cdd:cd16611     1 LTEELHCPLCLDFFRDPVMLSCGHNFCQSCITGFWELQAEdtTCPECRELCQYR 54

RING finger, HC subclass, found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also known as RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22, and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression, and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated (FHA) domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2462553801   8 EKLTCAICLGLYQDPVTL-PCGHNFCGACIRDWWDRCGKACPECR 51
Cdd:cd16503     1 ENLTCSICQDLLHDCVSLqPCMHNFCAACYSDWMERSNTECPTCR 45

PRY/SPRY domain of TRIM18/MID1, also known as FXY or RNF59; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is at the C-terminus of the overall domain architecture of MID1 (also known as FXY, RNF59, TRIM18) gene represented by a RING finger domain (RING), two B-box motifs (BBOX), coiled-coil C-terminal to Bbox domain (BBC) and fibronectin type 3 domain (FN3). Mutations in the human MID1 gene result in X-linked Opitz G/BBB syndrome (OS), a disorder affecting development of midline structures, causing craniofacial, urogenital, gastrointestinal and cardiovascular abnormalities. A unique MID1 gene mutation located in a variable loop in the SPRY domain alters conformation of the binding pocket and may affect the binding affinity to the PRY/SPRY domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 392 FDPVSANRHFYLSRQDQQVKH----CRQSRGPGGPGSFELWQVQCAQSFQAGHHYWEVRASDHS-VTLGVSYPQLPRcrl 466
Cdd:cd12892     4 LDPKSAHRKLKVSHDNLTVERdetsSKKSHTPERFTSQGSYGVAGNVFIDSGRHYWEVVISGSTwYAIGIAYKSAPK--- 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 467 gphTDNIGRGPCSWGLCVQEDSLQAWHNGEAQRL-PGVSGRLLGMDLDLASGCLTFYSlEPQTQPLYTFHALFNQPLTPV 545
Cdd:cd12892    81 ---HEWIGKNSASWVLCRCNNNWVVRHNSKEIPIePSPHLRRVGILLDYDNGSLSFYD-ALNSIHLYTFDIAFAQPVCPT 156

                  .
gi 2462553801 546 F 546
Cdd:cd12892   157 F 157

PRY/SPRY domain of tripartite motif-binding protein 60 and 75 (TRIM60 and TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM60 and TRIM75, both composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM60 domain is also known as RING finger protein 33 (RNF33) or 129 (RNF129). Based on its expression profile, RNF33 likely plays an important role in the spermatogenesis process, the development of the pre-implantation embryo, and in testicular functions; Rnf33 is temporally transcribed in the unfertilized egg and the pre-implantation embryo, and is permanently silenced before the blastocyst stage. Mice experiments have shown that RNF33 associates with the cytoplasmic motor proteins, kinesin-2 family members 3A (KIF3A) and 3B (KIF3B), suggesting possible contribution to cargo movement along the microtubule in the expressed sites. TRIM75, also known as Gm794, has a single site of positive selection in its RING domain associated with E3 ubiquitin ligase activity. It has not been detectably expressed experimentally due to their constant turnover by the proteasome, and therefore not been characterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 389 NLTFDPVSANRHFYLSRQDQQVKHCRQSRG-PGGPGSFELW-QVQCAQSFQAGHHYWEVRASDHSV-TLGVSYPQLPRcr 465
Cdd:cd15817     1 DLILDPETAHPNLIVSEDRKAVRYRRMKPNcPYDPRRFTVYpAVLGSEGFDSGRHFWEVEVGGKGEwILGVCKDSLPR-- 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 466 lgphtdNIGRGPCSWGLC----VQEDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLEPQTQpLYTFHALFNQP 541
Cdd:cd15817    79 ------NAQDPPSPLGGCwqigRYMSGYVASGPKTTQLLPVVKPSRIGIFLDYELGEVSFYNMNDRSH-LYTFTDTFTGK 151

                         170
                  ....*....|....*..
gi 2462553801 542 LTPVFWL-LEGRTLTLC 557
Cdd:cd15817   152 LIPYFYVgPDSEPLTIC 168

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        40
                  ....*....|....*....|....*....|....*....|.
gi 2462553801  10 LTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKACPEC 50
Cdd:cd16449     1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

first RING finger, HC subclass, found in Arabidopsis thaliana ORTHRUS and similar proteins; This subfamily includes Arabidopsis thaliana ORTHRUS 1-5. They are E3 ubiquitin-protein ligases that may participate in CpG methylation-dependent transcriptional regulation and/or epigenetic transcriptional silencing. ORTHRUS 1 mediates ubiquitination with the E2 ubiquitin-conjugating enzymes UBC11, UBC8 and UBC8 homologs (e.g. UBC10, UBC11, UBC28 and UBC29) but not with UBC27, UBC30, UBC32, UBC34 and UBC36. ORTHRUS 2 and 5 mediate ubiquitination with the E2 ubiquitin-conjugating enzyme UBC11. ORTHRUS 1 and 2 promote methylation-mediated gene silencing leading, for example, to early flowering. They can bind to CpG, CpNpG, and CpNpN DNA motifs, with a strong preference for methylated forms, and with highest affinity for CpG substrates. Members of this subfamily contain two typical C3HC4-type RING-HC fingers. This model corresponds to the first one.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2462553801   8 EKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKACPECREPFP 55
Cdd:cd23138     1 DELNCSFCMQLPERPVTTPCGHNFCLKCFQKWMGQGKKTCGTCRSPIP 48

Fibronectin type III and SPRY containing 1 (FSD1) domain includes PRY at the N-terminus; This domain is part of the fibronectin type III and SPRY domain containing 1 (FSD1) and FSD1-like (FSD1L) proteins. These are centrosome-associated proteins that are characterized by an N-terminal coiled-coil region downstream of B-box (BBC) domain, a central fibronectin type III (FN3) domain, and C-terminal repeats in PRY/SPRY domain. The FSD1 protein associates with a subset of microtubules and may be involved in the stability and organization of microtubules during cytokinesis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 438 AGHHYWEVRASD--HSVTLGVSYPQLPRcrlgphTDNIGRGPCSWGLCVQ---EDSLQAWHNGEAQRLPGVSGRLLGMDL 512
Cdd:cd12901    84 GGQHYWEVRAQKdsKAFSVGVAYRSLGK------FDQLGKTNASWCLHVNnwlQNSFAAKHNNKAKTLDVPVPDRIGVYC 157

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2462553801 513 DLASGCLTFYSLEPQtQPLYTFHALFNQPLTPVF 546
Cdd:cd12901   158 DFDEGQLSFYNARTK-QLLHTFKMKFTQPVLPAF 190

PRY/SPRY domain in tripartite motif-binding protein 15 (TRIM15); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of tripartite motif-containing protein 15 (TRIM15), also referred to as RING finger protein 93 (RNF93) or Zinc finger protein B7 or 178 (ZNFB7 or ZNF178). TRIM15 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. The PRY and SPRY/B30.2 domains can function as immune defense components and in pathogen sensing. TRIM15 has been shown to regulate inflammatory and innate immune signaling, in addition to displaying antiviral activities. Down-regulation of TRIM15, as well as TRIM11, enhances virus release, suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells. TRIM15 is also a regulatory component of focal adhesion turnover and cell migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 390 LTFDPVSANRHFYLSRQDQQVKHCRQSRG-PGGPGSFE-LWQVQCAQSFQAGHHYWEV---RASDHSVTLGVSYPQLPR- 463
Cdd:cd15826     2 VTLDPQTASGSLVLSEDRKSVRYTRQKQNlPDSPLRFDgLPAVLGSPGFSSGRHRWQVevqLGDGGGCTVGVAGESVRRk 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 464 CRLGPHTDNigrgpCSWGLCVQEDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLEPQTqPLYTFHALFNQPLT 543
Cdd:cd15826    82 GEMGLSAED-----GVWAVILSHQQCWASTSPGTDLPLSEIPRRVGVALDYEAGTVTLTNAETQE-PIFTFTASFSGKVF 155

                         170
                  ....*....|....
gi 2462553801 544 PVFWLL-EGRTLTL 556
Cdd:cd15826   156 PFFAVWkKGSRLTL 169

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM41, TRIM52 and similar proteins; TRIM41 and TRIM52, two closely related tripartite motif-containing proteins, have dramatically expanded RING domains compared with the rest of the TRIM family proteins. TRIM41 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. In contrast, TRIM52 lacks the putative viral recognition SPRY/B30.2 domain, and thus has been classified to the C-V subclass of the TRIM family that contains only RBCC domains. TRIM41, also known as RING finger-interacting protein with C kinase (RINCK), is an E3 ubiquitin-protein ligase that promotes the ubiquitination of protein kinase C (PKC) isozymes in cells. It specifically recognizes the C1 domain of PKC isozymes. It controls the amplitude of PKC signaling by controlling the amount of PKC in the cell. TRIM52, also known as RING finger protein 102 (RNF102), is encoded by a novel, noncanonical antiviral TRIM52 gene in primate genomes with unique specificity determined by the rapidly evolving RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2462553801   7 EEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWdrcGKACPECREPFP 55
Cdd:cd16602     1 QEEAVCAICLDYFKDPVSIGCGHNFCRVCVTQLW---GFTCPQCRKSFP 46

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2462553801   6 LEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKA-CPECREPfPDGAELRRNVALSGVLE 71
Cdd:cd16599     1 FKEELLCPICYEPFREAVTLRCGHNFCKGCVSRSWERQPRApCPVCKEA-SSSDDLRTNHTLNNLVE 66

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 2462553801  12 CAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKA--CPEC 50
Cdd:cd16601     4 CSLCKEYLKDPVIIECGHNFCRACITRFWEELDGDfpCPQC 44

RING finger, HC subclass, found in tripartite motif-containing protein TRIM21 and similar proteins; TRIM21, also known as 52 kDa Ro protein, 52 kDa ribonucleoprotein autoantigen Ro/SS-A, Ro(SS-A), RING finger protein 81 (RNF81), or Sjoegren syndrome type A antigen (SS-A), is a ubiquitously expressed E3 ubiquitin-protein ligase and a high affinity antibody receptor uniquely expressed in the cytosol of mammalian cells. As a cytosolic Fc receptor, TRIM21 binds the Fc of virus-associated antibodies and targets the complex in the cytosol for proteasomal degradation in a process known as antibody-dependent intracellular neutralization (ADIN), and provides an intracellular immune response to protect host defense against pathogen infection. It shows remarkably broad isotype specificity as it does not only bind IgG, but also IgM and IgA. Moreover, TRIM21 promotes the cytosolic DNA sensor cGAS and the cytosolic RNA sensor RIG-I sensing of viral genomes during infection by antibody-opsonized virus. It stimulates inflammatory signaling and activates innate transcription factors, such as nuclear factor-kappaB (NF-kappaB). TRIM21 also plays an essential role in p62-regulated redox homeostasis, suggesting it may be a viable target for treating pathological conditions resulting from oxidative damage. Furthermore, TRIM21 may have implications for various autoimmune diseases associated with uncontrolled antiviral signaling through the regulation of Nmi-IFI35 complex-mediated inhibition of innate antiviral response. TRIM21 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2462553801   1 MAAQLLEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKACPECREPF 54
Cdd:cd16596     1 ARLTMMWEEVTCPICLDPFVEPVSIECGHSFCQECISQVGKGGGSVCPVCRQRF 54

PRY/SPRY domain of tripartite motif-binding protein 75 (TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM75, also known as Gm794. TRIM75 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM75 has a single site of positive selection in its RING domain associated with E3 ubiquitin ligase activity. It has not been detectably expressed experimentally due to their constant turnover by the proteasome, and therefore not been characterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 381 RKLWQNYR-NLTFDPVSANRHFYLSRQDQQVKHC-RQSRGPGGPGSFELWQVQCA-QSFQAGHHYWEVRASDHSV-TLGV 456
Cdd:cd15829    11 QKIIKKFRvDVTLDPETAHPNLLVSEDKKCVTFTkKKQRVPDSPKRFTVNPVVLGfPGFHSGRHFWEVEVGDKPEwAVGV 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801 457 SYPQLPR-CRLGPhtdnigRGP-CSWGLCVQEDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLePQTQPLYTF 534
Cdd:cd15829    91 CKDSLSTkARRPP------SGQqGCWRIQLQGGDYDAPGAVPPPLLLEVKPRGIGVFLDYELGEISFYNM-PEKSHIHTF 163

                         170       180
                  ....*....|....*....|....
gi 2462553801 535 HALFNQPLTPVFWL-LEGRTLTLC 557
Cdd:cd15829   164 TDTFSGPLRPYFYVgPDSKPLRIC 187

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462553801  439 GHHYWEVRASD-HSVTLGVSYPQLPRcrlgPHTDNIGRGPCSWGLCVqeDSLQAWHNGEAQRLP---GVSGRLLGMDLDL 514
Cdd:smart00449   2 GRHYFEVEIGDgGHWRVGVATKSVPR----GYFALLGEDKGSWGYDG--DGGKKYHNSTGPEYGlplQEPGDVIGCFLDL 75

                           90       100       110
                   ....*....|....*....|....*....|....
gi 2462553801  515 ASGCLTFYSLEPQTQPLYTFHALFNQPLTPVFWL 548
Cdd:smart00449  76 EAGTISFYKNGKYLHGLAFFDVKFSGPLYPAFSL 109

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 2462553801   12 CAICLGLY-QDPVTLPCGHNFCGACIRDWWDRCGKACPEC 50
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40