RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQaaIGETYYCPQCREAFSSRPRLCKNVILGEMV 134
Cdd:cd16597   2 LEEELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQ--HGSEYSCPQCRATFPRRPELHKNTVLRNIV 69

B-box-type 2 zinc finger found in tripartite motif-containing proteins, TRIM16, TRIM29, TRIM47 and similar proteins; This family includes a group of tripartite motif-containing proteins, such as TRIM16, TRIM29 and TRIM47. TRIM16, also termed estrogen-responsive B box protein (EBBP), is a regulator that may play a role in the regulation of keratinocyte differentiation. It may also act as a tumor suppressor through affecting cell proliferation and migration or tumorigenicity in carcinogenesis. TRIM29, also termed ataxia telangiectasia group D-associated protein (ATDC), plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. TRIM16 and TRIM29 belong to an unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers and thus lack the characteristic tripartite (RING (R), B-box, and coiled coil (CC)) RBCC motif. TRIM47 belongs to the C-IV subclass of TRIM 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, Bbox1 and Bbox2, and two coiled coil domains, 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 85702085 209 RLCRKHRKLRQLYCRTEGSCVCGACLLEEHKNHDTTPLEDERARKE 254
Cdd:cd19769   1 RVCPIHKKPLELFCRTDQMCICELCAKEEHRGHDVVTVEEEREKKE 46

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQaaIGETYYCPQCREAFSSRPRLCKNVILGEMV 134
Cdd:cd16597   2 LEEELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQ--HGSEYSCPQCRATFPRRPELHKNTVLRNIV 69

B-box-type 1 zinc finger found in tripartite motif-containing proteins, TRIM8, TRIM16, TRIM25, TRIM29, TRIM44, TRIM47 and similar proteins; This family includes a group of tripartite motif-containing proteins, including TRIM8, TRIM16, TRIM25, TRIM29, TRIM44 and TRIM47. TRIM8, also known as glioblastoma-expressed RING finger protein (GERP) or RING finger protein 27 (RNF27), is a probable E3 ubiquitin-protein ligase that may promote proteasomal degradation of suppressor of cytokine signaling 1 (SOCS1) and further regulate interferon-gamma signaling. It functions as a new p53 modulator that stabilizes p53, impairing its association with MDM2 and inducing the reduction of cell proliferation. TRIM16, also termed estrogen-responsive B box protein (EBBP), may play a role in the regulation of keratinocyte differentiation. It may also act as a tumor suppressor by affecting cell proliferation and migration or tumorigenicity in carcinogenesis. TRIM25, also termed estrogen-responsive finger protein (EFP), or ubiquitin/ISG15-conjugating enzyme TRIM25, or zinc finger protein 147 (ZNF147), or E3 ubiquitin/ISG15 ligase TRIM25, is induced by estrogen and is particularly abundant in placenta and uterus. It has been implicated in cell proliferation, protein modification, and the retinoic acid inducible gene I (RIG-I)-mediated antiviral signaling pathway. It functions as an E3-ubiquitin ligase able to transfer ubiquitin and ISG15 to target proteins. TRIM29, also termed ataxia telangiectasia group D-associated protein (ATDC), plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. TRIM44, also termed protein DIPB, functions as a critical regulator in tumor metastasis and progression. TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. The TRIM (tripartite motif) family of proteins are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox1 and Bbox2, and a coiled coil domain. The type 1 B-box (Bbox1) zinc finger is characterized by a C6H2 zinc-binding consensus motif.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 85702085 158 PCDFCSPQK-LRAAKSCLQCVASLCEKHLRSHFEDQLFQDHQLLDP 202
Cdd:cd19802   1 LCDFCDPGKaLKAVKSCLTCEASLCEIHLRPHLESPALKSHQLVEP 46

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 85702085   500 HYWEAEV---SNSWMCLGVTYRRSPPLSGRPrrnivylLGRNPYSWCleWDSLKFSVWHNNTQTvLHGSYHHT----LGV 572
Cdd:pfam00622   2 HYFEVEIfgqDGGGWRVGWATKSVPRKGERF-------LGDESGSWG--YDGWTGKKYWASTSP-LTGLPLFEpgdvIGC 71

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 85702085   573 ALDFRTGCLSFYSVAGDvnLLYRFLT-SFLEPLYPAVMVSSGASLTL 618
Cdd:pfam00622  72 FLDYEAGTISFTKNGKS--LGYAFRDvPFAGPLFPAVSLGAGEGLKF 116

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085    50 TPLHLLMGsnssqhmLEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAAigetyyCPQCREAFSSRpRLCKNVI 129
Cdd:TIGR00599  15 TPIPSLYP-------LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQPK------CPLCRAEDQES-KLRSNWL 80

                          90
                  ....*....|...
gi 85702085   130 LGEMVACFTQAKS 142
Cdd:TIGR00599  81 VSEIVESFKNLRP 93

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 85702085   208 NRLCRKH-RKLRQLYCRTEGSCVCGACLLEEHKNHDTTPL 246
Cdd:pfam00643   3 ERLCPEHeEEPLTLYCNDCQELLCEECSVGEHRGHTVVPL 42

B-Box-type zinc finger;

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 85702085    209 RLCRKHR-KLRQLYCRTEGSCVCGACLLEEHKNHDTTPL 246
Cdd:smart00336   4 PKCDSHGdEPAEFFCEECGALLCRTCDEAEHRGHTVVLL 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 85702085 444 LNFDPCTASEELFLFKETHSVLNLGILLEPSttnSPLPGFKQWPQVLCCPGLSEGCHYWEAEVSN-SWMCLGVTYRRSPp 522
Cdd:cd12874   1 LTFDPDTAHLNLILSDDLRSVRVGDISQHPP---EPPPRFFECWQVLGSQSFSSGRHYWEVDVQDdSSWYVGVTYKSLP- 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 523 lsgrpRRNIVYLLGRNPYSWCLEWDSLKFSVWHNNTQTVLHGSYHHTLGVALDFRTGCLSFYSVAGDVNLLYRFLTSFLE 602
Cdd:cd12874  77 -----RKGKMSNLGRNNGSWCLEWRENEFSAWHNNPETRLPVTPPRRLGVFLDCDGGSLSFYGVTDGVQLLYTFKAKFTE 151

                       170
                ....*....|....*..
gi 85702085 603 PLYPAVMVSSGASLTLK 619
Cdd:cd12874 152 PLYPAFWLGEGSTLSIC 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 85702085 434 RKTLLQNYCNLNFDPCTASEELFLFKETHSVLNlgillepSTTNSPLPG----FKQWPQVLCCPGLSeGCHYWEAEVSNS 509
Cdd:cd16040   1 REEFLKYACQLTLDPNTAHRNLSLSEGNRKVTR-------VKEEQPYPDhperFDYWPQVLCREGLS-GRCYWEVEWSGG 72

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 510 WMCLGVTYRrspplsGRPRRNIVY--LLGRNPYSWCLEWDSLKFSVWHNN--TQTVLHGSYHHTLGVALDFRTGCLSFYS 585
Cdd:cd16040  73 GVDIAVAYK------GISRKGDGDdsRFGYNDKSWSLECSPSGYSFWHNNkkTEISVPSSSSSRVGVYLDHSAGTLSFYS 146

                       170       180       190
                ....*....|....*....|....*....|...
gi 85702085 586 VAGDVNLLYRFLTSFLEPLYPAVMVSSGASLTL 618
Cdd:cd16040 147 VSDTMTLLHTVQTTFTEPLYPGFGVGYGSSVKL 179

PRY/SPRY domain in tripartite motif-containing protein 16 (TRIM16); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM16 and TRIM-like proteins. TRIM16 (also known as estrogen-responsive B box protein or EBBP) does not possess a RING domain like the other TRIM proteins, but contains two B-box domains and can heterodimerize with other TRIM proteins such as TRIM24, Promyelocytic leukemia (PML) protein and Midline-1 (MID1 or TRIM18). It is a regulator of keratinocyte differentiation and a tumor suppressor in retinoid-sensitive neuroblastoma. It has been shown that loss of TRIM16 expression plays an important role in the development of cutaneous squamous cell carcinoma (SCC) and is a determinant of retinoid sensitivity. TRIM16 also has E3 ubiquitin ligase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 434 RKTLLQNYCNLNFDPCTASEELFLFKETHSVLNlgillepsTT--NSPLPG----FKQWPQVLCCPGLSEGCHYWEAEVS 507
Cdd:cd12890   1 RDDFLKYAYPLTFDPDTAHRYLRLTEDNRKVTN--------TTpwEHPYPDhperFEHWRQVLSQQSLYLGRYYFEVEIS 72

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 508 NSWMCLGVTY----RRSPPLSGRprrnivylLGRNPYSWCLEWDSLKFSVWHNNTQTVLHGSYHHTLGVALDFRTGCLSF 583
Cdd:cd12890  73 GEGTYVGLTYksidRKGSESNSC--------ISGNNFSWCLQWNGKEFSAWHSDVETPLKKGPFTRLGIYLDYPGGTLSF 144

                       170       180
                ....*....|....*....|....*....
gi 85702085 584 YSVAGD-VNLLYRFLTSFLEPLYPAVMVS 611
Cdd:cd12890 145 YGVEDDgMTLLHKFQCKFTEPLYPAFWLS 173

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQaaIGETYYCPQCREAFSSRPRLCKNVILGEMV 134
Cdd:cd16597   2 LEEELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQ--HGSEYSCPQCRATFPRRPELHKNTVLRNIV 69

PRY/SPRY domain in tripartite motif-containing proteins 1, 9, 18, 36, 46, 67,76 (TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67, TRIM76); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class I TRIM proteins, including TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67 and TRIM76. TRIM1 (also known as MID2) and its close homolog, TRIM18 (also known as MID1), both contain a B30.2-like domain at their C-terminus and a single fibronectin type III (FN3) motif between it and their N-terminal RBCC domain. Their coiled-coil motifs mediate both homo- and heterodimerization, a prerequisite for association of the rapamycin-sensitive PP2A regulatory subunit Alpha 4 with microtubules. Mutations in TRIM18 have shown to cause Opitz syndrome, a disorder causing congenital anomalies such as cleft lip and palate as well as heart defects. TRIM9 is expressed mainly in the cerebral cortex, and functions as an E3 ubiquitin ligase. Its immunoreactivity is severely decreased in affected brain areas in Parkinson's disease and dementia with Lewy bodies, possibly playing an important role in the regulation of neuronal function and participating in pathological process of Lewy body disease through its ligase. TRIM36 interacts with centromere protein-H, one of the kinetochore proteins and possibly associates with chromosome segregation; an excess of TRIM36 may cause chromosomal instability. TRIM46 has not yet been characterized. TRIM67 negatively regulates Ras activity via degradation of 80K-H, leading to neural differentiation, including neuritogenesis. TRIM76 (also known as cardiomyopathy-associated protein 5 or CMYA5) is a muscle-specific member of the TRIM superfamily, but lacks the RING domain. It is possibly involved in protein kinase A signaling as well as vesicular trafficking. It has also been implicated in Duchenne muscular dystrophy and cardiac disease. 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 85702085 445 NFDPCTASEELFLFKETHSVLNLGILLEPSTTNSPlPGFKQWPQVLCCPGLSEGCHYWEAEVSNS-WMCLGVTYRRSPPL 523
Cdd:cd13734   2 KLDPKTAHRKLRLSNDNLTVEYDPEGSKDQAAVLP-RRFTGSPAVLGDVAISSGRHYWEVSVSRStSYRVGVAYKSAPRD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 524 SgrprrnivyLLGRNPYSWCLEWDSLKFSVWHNNTQTVLHGSYH-HTLGVALDFRTGCLSFYSvAGDVNLLYRFLTSFLE 602
Cdd:cd13734  81 E---------DLGKNSTSWCLSRDNNRYTARHDGKVVDLRVTGHpARIGVLLDYDNGTLSFYD-AESKQHLYTFHVDFEG 150

                       170
                ....*....|....*.
gi 85702085 603 PLYPAVMVSSGaSLTL 618
Cdd:cd13734 151 PVCPAFAVWNG-SLTL 165

RING finger, HC subclass, found in tripartite motif-containing protein 77 (TRIM77) and similar proteins; TRIM77 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 two consecutive zinc-binding domains, a C3HC4-type RING-HC finger and Bbox2, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 85702085  66 EDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAAIgetYYCPQCREAFSSRP 122
Cdd:cd16543   1 EDQLTCSICLDLLKDPVTIPCGHSFCMNCITLLWDRKQGV---PSCPQCRESFPPRP 54

PRY/SPRY domain of tripartite motif-binding protein 14 (TRIM14); This is a TRIM14 domain family 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. TRIM14 domains have yet to be characterized. These B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. It belongs to Class IV TRIM protein family which has members involved in antiviral immunity at various levels of interferon signaling cascade.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 477 NSPLPGFKQWpQVLCCPGLSEGCHYWEAEVSNS----WmcLGVTY----RRSPPLSGRprrnivylLGRNPYSWCLEWDS 548
Cdd:cd13738  32 CPPQRFDKLW-QVLSRDSFFSGRHYWEVDLQEAgagwW--VGAAYpsigRKGDSEAAR--------LGWNRQSWCLKRYD 100

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 85702085 549 LKFSVWHNNTQT-VLHGSYHHTLGVALDFRTGCLSFYSVAGDVNLLYRFLTSFLEPLYPAVMVSSGA 614
Cdd:cd13738 101 LEYWAFHDGQRSrLRPEDDPDRLGVFLDYEAGILSFYDVTGGMTHLHTFRATFQEPLYPALRLWEGS 167

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085  66 EDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWdHQAAIGeTYYCPQCREAFSSRPRLC 125
Cdd:cd16609   1 EEELTCSICLGLYQDPVTLPCQHSFCRACIEDHW-RQKDEG-SFSCPECRAPFPEGPTLE 58

B-box-type 1 zinc finger found in tripartite motif-containing proteins, TRIM8, TRIM16, TRIM25, TRIM29, TRIM44, TRIM47 and similar proteins; This family includes a group of tripartite motif-containing proteins, including TRIM8, TRIM16, TRIM25, TRIM29, TRIM44 and TRIM47. TRIM8, also known as glioblastoma-expressed RING finger protein (GERP) or RING finger protein 27 (RNF27), is a probable E3 ubiquitin-protein ligase that may promote proteasomal degradation of suppressor of cytokine signaling 1 (SOCS1) and further regulate interferon-gamma signaling. It functions as a new p53 modulator that stabilizes p53, impairing its association with MDM2 and inducing the reduction of cell proliferation. TRIM16, also termed estrogen-responsive B box protein (EBBP), may play a role in the regulation of keratinocyte differentiation. It may also act as a tumor suppressor by affecting cell proliferation and migration or tumorigenicity in carcinogenesis. TRIM25, also termed estrogen-responsive finger protein (EFP), or ubiquitin/ISG15-conjugating enzyme TRIM25, or zinc finger protein 147 (ZNF147), or E3 ubiquitin/ISG15 ligase TRIM25, is induced by estrogen and is particularly abundant in placenta and uterus. It has been implicated in cell proliferation, protein modification, and the retinoic acid inducible gene I (RIG-I)-mediated antiviral signaling pathway. It functions as an E3-ubiquitin ligase able to transfer ubiquitin and ISG15 to target proteins. TRIM29, also termed ataxia telangiectasia group D-associated protein (ATDC), plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. TRIM44, also termed protein DIPB, functions as a critical regulator in tumor metastasis and progression. TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. The TRIM (tripartite motif) family of proteins are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox1 and Bbox2, and a coiled coil domain. The type 1 B-box (Bbox1) zinc finger is characterized by a C6H2 zinc-binding consensus motif.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 85702085 158 PCDFCSPQK-LRAAKSCLQCVASLCEKHLRSHFEDQLFQDHQLLDP 202
Cdd:cd19802   1 LCDFCDPGKaLKAVKSCLTCEASLCEIHLRPHLESPALKSHQLVEP 46

B-box-type 2 zinc finger found in tripartite motif-containing proteins, TRIM16, TRIM29, TRIM47 and similar proteins; This family includes a group of tripartite motif-containing proteins, such as TRIM16, TRIM29 and TRIM47. TRIM16, also termed estrogen-responsive B box protein (EBBP), is a regulator that may play a role in the regulation of keratinocyte differentiation. It may also act as a tumor suppressor through affecting cell proliferation and migration or tumorigenicity in carcinogenesis. TRIM29, also termed ataxia telangiectasia group D-associated protein (ATDC), plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. TRIM16 and TRIM29 belong to an unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers and thus lack the characteristic tripartite (RING (R), B-box, and coiled coil (CC)) RBCC motif. TRIM47 belongs to the C-IV subclass of TRIM 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, Bbox1 and Bbox2, and two coiled coil domains, 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 85702085 209 RLCRKHRKLRQLYCRTEGSCVCGACLLEEHKNHDTTPLEDERARKE 254
Cdd:cd19769   1 RVCPIHKKPLELFCRTDQMCICELCAKEEHRGHDVVTVEEEREKKE 46

RING finger, HC subclass, found in tripartite motif-containing protein 47 (TRIM47) and similar proteins; TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), 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, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. It plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. This subfamily also includes RING finger protein 135 (RNF135). RNF135, also known as RIG-I E3 ubiquitin ligase (REUL) or Riplet, is a widely expressed E3 ubiquitin-protein ligase that consists of an N-terminal C3HC4-type RING-HC finger and C-terminal B30.2/SPRY and PRY motifs, but lacks the B-box and coiled-coil domains that are also typically present in TRIM proteins. RNF135 serves as a specific retinoic acid-inducible gene-I (RIG-I)-interacting protein that ubiquitinates RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity to produce antiviral type-I interferon (IFN) during the early phase of viral infection. It also has been identified as a bio-marker and therapy target of glioblastoma. It associates with the ERK signal transduction pathway and plays a role in glioblastoma cell proliferation, migration and cell cycle.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 85702085  71 CPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAaiGETYYCPQCREAFS 119
Cdd:cd16604   3 CPICLDLLKDPVTLPCGHSFCMGCLGALWGAGR--GGRASCPLCRQTFP 49

B-box-type 1 zinc finger found in tripartite motif-containing proteins, TRIM25, TRIM47 and similar proteins; The family includes tripartite motif-containing proteins, TRIM25 and TRIM47, both of which belong 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, Bbox1 and Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. The type 1 B-box (Bbox1) zinc finger is characterized by a C6H2 zinc-binding consensus motif. TRIM25, also termed estrogen-responsive finger protein (EFP), or ubiquitin/ISG15-conjugating enzyme TRIM25, or zinc finger protein 147 (ZNF147), or E3 ubiquitin/ISG15 ligase TRIM25, is induced by estrogen and is particularly abundant in placenta and uterus. It has been implicated in cell proliferation, protein modification, and the retinoic acid inducible gene I (RIG-I)-mediated antiviral signaling pathway. It functions as an E3-ubiquitin ligase able to transfer ubiquitin and ISG15 to target proteins. TRIM47, also known as gene overexpressed in astrocytoma protein (GOA) or RING finger protein 100 (RNF100), plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 85702085 159 CDFCSPQKLRAAKSCLQCVASLCEKHLRSHFEDQLFQDHQLLDPVWDL 206
Cdd:cd19842   2 CDLCLGRELAAAKTCLTCLASFCPEHLEPHLSSPAFRSHRLCPPERDL 49

B-box-type 1 zinc finger found in tripartite motif-containing protein 29 (TRIM29) and similar proteins; TRIM29, also termed ataxia telangiectasia group D-associated protein (ATDC), plays a crucial role in the regulation of macrophage activation in response to viral or bacterial infections within the respiratory tract. TRIM29 belongs to an unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers and thus lack the characteristic tripartite (RING (R), B-box, and coiled coil (CC)) RBCC motif. The type 1 B-box (Bbox1) zinc finger is characterized by a C6H2 zinc-binding consensus motif.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 85702085 157 VPCDFCSPQKLRAAKSCLQCVASLCEKHLRSHFEDQLFQDHQLLDPV 203
Cdd:cd19840   1 VLCDSCIDNKQKAVKSCLVCQASFCELHLKPHLEGAAFRDHQLLEPI 47

RING finger, HC subclass, found in tripartite motif-containing protein 62 (TRIM62) and similar proteins; TRIM62, also known as Ductal Epithelium Associated Ring Chromosome 1 (DEAR1), is a cytoplasmic E3 ubiquitin-protein ligase that was identified as a dominant regulator of acinar morphogenesis in the mammary gland. It is implicated in the inflammatory response of immune cells by regulating the Toll-like receptor 4 (TLR4) signaling pathway, leading to increased activity of the activator protein 1 (AP-1) transcription factor in primary macrophages. It is also involved in muscular protein homeostasis, especially during inflammation-induced atrophy, and may play a role in the pathogenesis of ICU-acquired weakness (ICUAW) by activating and maintaining inflammation in myocytes. Moreover, TRIM62 facilitates K27-linked poly-ubiquitination of CARD9 and also regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. It also functions as a chromosome 1p35 tumor suppressor and negatively regulates transforming growth factor beta (TGFbeta)-driven epithelial-mesenchymal transition (EMT) by binding to and promoting the ubiquitination of SMAD3, a major effector of TGFbeta-mediated EMT. TRIM62 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 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQaaigETYYCPQCREAF 118
Cdd:cd16608   3 LKDELLCSICLSIYQDPVSLGCEHYFCRQCITEHWSRS----EHRDCPECRRTF 52

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 85702085 495 LSEGCHYWEAEVSNS-WMCLGVTYRRSPPLSgrprrnivyLLGRNPYSWCLEWDSLKFSVWHNNTQTVLHGSYH-HTLGV 572
Cdd:cd12892  52 IDSGRHYWEVVISGStWYAIGIAYKSAPKHE---------WIGKNSASWVLCRCNNNWVVRHNSKEIPIEPSPHlRRVGI 122

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 85702085 573 ALDFRTGCLSFYSVAGDVNlLYRFLTSFLEPLYPAVMV 610
Cdd:cd12892 123 LLDYDNGSLSFYDALNSIH-LYTFDIAFAQPVCPTFTV 159

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 85702085  68 QVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAAigeTYYCPQC 114
Cdd:cd16601   1 EASCSLCKEYLKDPVIIECGHNFCRACITRFWEELDG---DFPCPQC 44

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 85702085   500 HYWEAEV---SNSWMCLGVTYRRSPPLSGRPrrnivylLGRNPYSWCleWDSLKFSVWHNNTQTvLHGSYHHT----LGV 572
Cdd:pfam00622   2 HYFEVEIfgqDGGGWRVGWATKSVPRKGERF-------LGDESGSWG--YDGWTGKKYWASTSP-LTGLPLFEpgdvIGC 71

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 85702085   573 ALDFRTGCLSFYSVAGDvnLLYRFLT-SFLEPLYPAVMVSSGASLTL 618
Cdd:pfam00622  72 FLDYEAGTISFTKNGKS--LGYAFRDvPFAGPLFPAVSLGAGEGLKF 116

RING finger, HC subclass, found in tripartite motif-containing protein TRIM4 and similar proteins; TRIM4 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM4, also known as RING finger protein 87 (RNF87), is a cytoplasmic E3 ubiquitin-protein ligase that has recently evolved and is present only in higher mammals. It transiently interacts with mitochondria, induces mitochondrial aggregation and sensitizes the cells to hydrogen peroxide (H2O2) induced death. Its interaction with peroxiredoxin 1 (PRX1) is critical for the regulation of H2O2 induced cell death. Moreover, TRIM4 functions as a positive regulator of RIG-I-mediated type I interferon induction. It regulates the K63-linked ubiquitination of RIG-1 and assembly of antiviral signaling complex at the mitochondria.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWdhqAAIGETYYCPQCR 115
Cdd:cd16590   3 IQEELTCPICLDYFQDPVSIECGHNFCRGCLHRNW---APGGGPFPCPECR 50

SPRY domain in Ro-Ret family; This domain, named BSPRY, has been identified in the Ro-Ret family, since the protein is composed of a B-box, an alpha-helical coiled coil and a SPRY domain. The gene for BSPRY resides on human chromosome 9 and is specifically expressed in testis. The function of BSPRY is not known, but several related proteins of the RING-Box-coiled-coil (RBCC) family have been implicated in cell transformation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702085 483 FKQWPQVLCCPGLSEGCHYWEAEVSNSwmC---LGVTY----RRSPPLSGRprrnivylLGRNPYSWCLEWDSLKFSVWH 555
Cdd:cd12904  39 FDHWPNALASLSFSSGTHAWVVDVGKS--CaykVGVCYgsleRKGSGNEAR--------LGYNAFSWVFSRYDGEFSFSH 108

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 85702085 556 NNTQT---VLHGSyhHTLGVALDFRTGCLSFYSvAGDVNLLYRFLTSFLEPLYPAVMVS 611
Cdd:cd12904 109 NGQHVpleLLKCP--ARVGVLLDWPSQELLFYD-PDSCTVLHSHREAFAAPLLPVFAVA 164

RING finger, HC subclass, found in tripartite motif-containing protein 10 (TRIM10) and similar proteins; TRIM10, also known as B30-RING finger protein (RFB30), RING finger protein 9 (RNF9), or hematopoietic RING finger 1 (HERF1), is a novel hematopoiesis-specific RING finger protein required for terminal differentiation of erythroid cells. TRIM10 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 85702085  65 LEDQVLCPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAAIGET-YYCPQCREAF 118
Cdd:cd16593   2 LADEVNCPICQGTLREPVTIDCGHNFCRACLTRYCEIPGPDLEEpPTCPLCKEPF 56

second RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the second RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 85702085  71 CPICLEVFCNPVTTACGHNFCMTCLQNFWDHqaaigeTYYCPQCRE 116
Cdd:cd16514   4 CSLCLRLLYEPVTTPCGHTFCRACLERCLDH------SPKCPLCRT 43

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 85702085 498 GCHYWEAEVSNSW---MCLGVTyrrspplSGRPRRNIVYLLGRNPYSWCleWDSLKFSVWHNNTQTVLHGSY--HHTLGV 572
Cdd:cd11709   1 GKWYWEVRVDSGNgglIQVGWA-------TKSFSLDGEGGVGDDEESWG--YDGSRLRKGHGGSSGPGGRPWksGDVVGC 71

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 85702085 573 ALDFRTGCLSFYsVAG-DVNLLYRFLTSFLEPLYPAVMVSSGASLTL 618
Cdd:cd11709  72 LLDLDEGTLSFS-LNGkDLGVAFTNLFLKGGGLYPAVSLGSGQGVTI 117

zinc finger of C3HC4-type, RING; This is a family of primate-specific Ret finger protein-like (RFPL) zinc-fingers of the C3HC4 type. Ret finger protein-like proteins are primate-specific target genes of Pax6, a key transcription factor for pancreas, eye and neocortex development. This domain is likely to be DNA-binding. This zinc-finger domain together with the RDM domain, pfam11002, forms a large zinc-finger structure of the RING/U-Box superfamily. RING-containing proteins are known to exert an E3 ubiquitin protein ligase activity with the zinc-finger structure being mandatory for binding to the E2 ubiquitin-conjugating enzyme.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 85702085    71 CPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAaiGETYYCPQC 114
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQKEPD--GESLLCPQC 42

RING finger, HC subclass, found in tripartite motif-containing protein 38 (TRIM38) and similar proteins; TRIM38, also known as RING finger protein 15 (RNF15) or zinc finger protein RoRet, is an E3 ubiquitin-protein ligase that promotes K63- and K48-linked ubiquitination of cellular proteins and also catalyzes self-ubiquitination. It negatively regulates Tumor necrosis factor alpha (TNF-alpha)- and interleukin-1beta-triggered Nuclear factor-kappaB (NF-kappaB) activation by mediating lysosomal-dependent degradation of transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1)-binding protein (TAB)2/3, two critical components of the TAK1 kinase complex. It also inhibits TLR3/4-mediated activation of NF-kappaB and interferon regulatory factor 3 (IRF3) by mediating ubiquitin-proteasomal degradation of TNF receptor-associated factor 6 (Traf6) and NAK-associated protein 1 (Nap1), respectively. Moreover, TRIM38 negatively regulates TLR3-mediated interferon beta (IFN-beta) signaling by targeting ubiquitin-proteasomal degradation of TIR domain-containing adaptor inducing IFN-beta (TRIF). It functions as a valid target for autoantibodies in primary Sjogren's Syndrome. TRIM38 belongs 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, a B-box, and two coiled coil domains, 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 85702085  71 CPICLEVFCNPVTTACGHNFCMTCLQNFWDHQAAIG---ETYYCPQCREAF 118
Cdd:cd16600   8 CSICLQLMTEPVSINCGHSYCKRCIVSFLENQSQLEpglETFSCPQCRAPF 58