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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1916926375  11 EQFSCSICLDLLKDPVTIPCGHSYCMDCIKGCWDqDDHTGVYSCPQCRETFTSRPVLRRNTLLAEVVEK 79
Cdd:cd16597     4 EELTCSICLELFKDPVTLPCGHNFCGVCIEKTWD-SQHGSEYSCPQCRATFPRRPELHKNTVLRNIVEQ 71

B-box-type zinc finger superfamily; The B-box-type zinc finger is a short zinc binding domain of around 40 amino acid residues in length. It has been found in transcription factors, ribonucleoproteins and proto-oncoproteins, such as in TRIM (tripartite motif) proteins that consist of an N-terminal RING finger (originally called an A-box), followed by 1-2 B-box domains and a coiled-coil domain (also called RBCC for Ring, B-box, Coiled-Coil). The B-box-type zinc finger often presents in combination with other motifs, like RING zinc finger, NHL motif, coiled-coil or RFP domain in functionally unrelated proteins, most likely mediating protein-protein interactions. Based on different consensus sequences and the spacing of the 7-8 zinc-binding residues, B-box-type zinc fingers can be divided into two groups, type 1 (Bbox1: C6H2) and type 2 (Bbox2: CHC3H2).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1916926375 102 CDVCTGRKC-KAVKSCLECLVSYCETHLQVHNNINPGKKHKLIE 144
Cdd:cd19802     2 CDFCDPGKAlKAVKSCLTCEASLCEIHLRPHLESPALKSHQLVE 45

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 1916926375  11 EQFSCSICLDLLKDPVTIPCGHSYCMDCIKGCWDqDDHTGVYSCPQCRETFTSRPVLRRNTLLAEVVEK 79
Cdd:cd16597     4 EELTCSICLELFKDPVTLPCGHNFCGVCIEKTWD-SQHGSEYSCPQCRATFPRRPELHKNTVLRNIVEQ 71

associated with SPRY domains;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1916926375  382 SCQLTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGL 433
Cdd:smart00589   1 AVDVTLDPDTAHPYLLLSEDRRSVRYGDLKQSLPDNPERFDSYPCVLGSQGF 52

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 1916926375  15 CSICLDLLKDPVTIPCGHSYCMDCIKGCWdQDDHTGVYSCPQC 57
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQ-KEPDGESLLCPQC 42

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 1916926375 102 CDVCTGRKC-KAVKSCLECLVSYCETHLQVHNNINPGKKHKLIE 144
Cdd:cd19802     2 CDFCDPGKAlKAVKSCLTCEASLCEIHLRPHLESPALKSHQLVE 45

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375  186 TVSSAAERTEKQKELGATQRKFQQRIQEREKELQDLRQAVESLT---RSAQAAVEDSERIFTELIRSIERRRSEVKKLIR 262
Cdd:TIGR02168  668 TNSSILERRREIEELEEKIEELEEKIAELEKALAELRKELEELEeelEQLRKELEELSRQISALRKDLARLEAEVEQLEE 747

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1916926375  263 DQEKAALNQTEgvmerLEQEIAELRRRDAEL-EQLSHAEDHIHFLQ 307
Cdd:TIGR02168  748 RIAQLSKELTE-----LEAEIEELEERLEEAeEELAEAEAEIEELE 788

Autophagy protein 16 (ATG16); Autophagy is a ubiquitous intracellular degradation system for eukaryotic cells. During autophagy, cytoplasmic components are enclosed in autophagosomes and delivered to lysosomes/vacuoles. ATG16 (also known as Apg16) has been shown to be bind to Apg5 and is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 188 SSAAERTEKQKELGATQRK---FQQRIQEREKELQDLRqaveSLTRSAQAAVEDSERIFTELIRSIERRRSEVK---KLI 261
Cdd:pfam08614  54 SLEQLLAQLREELAELYRSrgeLAQRLVDLNEELQELE----KKLREDERRLAALEAERAQLEEKLKDREEELRekrKLN 129

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1916926375 262 RDQ--EKAAL----NQTEGVMERLEQEIAEL 286
Cdd:pfam08614 130 QDLqdELVALqlqlNMAEEKLRKLEKENREL 160

phosphodiesterase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 191 AERTEKQKELGATQ------RKFQQRIQEREKELQD----LRQAVESLTRSAQAA------VEDSERIFTELIRSIERRR 254
Cdd:PRK12704   51 AEAIKKEALLEAKEeihklrNEFEKELRERRNELQKlekrLLQKEENLDRKLELLekreeeLEKKEKELEQKQQELEKKE 130

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1916926375 255 SEVKKLIRDQEK-----AALNQTEG---VMERLEQ----EIAELRRR---DAELE 294
Cdd:PRK12704  131 EELEELIEEQLQeleriSGLTAEEAkeiLLEKVEEearhEAAVLIKEieeEAKEE 185

B-Box-type zinc finger;

                           10        20        30
                   ....*....|....*....|....*....|
gi 1916926375  155 SHHDKLLEIYCRTDKKCICYLCMVDQHRGH 184
Cdd:smart00336   8 SHGDEPAEFFCEECGALLCRTCDEAEHRGH 37

E3 ubiquitin-protein ligase RMA2; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1916926375  13 FSCSICLDLLKDPVTIPCGHSYCMDCIKGcW-----------DQDDHT-GVYSCPQCR 58
Cdd:PLN03208   19 FDCNICLDQVRDPVVTLCGHLFCWPCIHK-WtyasnnsrqrvDQYDHKrEPPKCPVCK 75

polarized growth protein Scy;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375  190 AAERTEKQKELGATQRKFQQRIQEREKELQDLRQAVESLTRSaqaAVEDSERIFTEL---IRSIERRRSEVKKLIRDQEK 266
Cdd:NF041483   567 AARQAEAAEELTRLHTEAEERLTAAEEALADARAEAERIRRE---AAEETERLRTEAaerIRTLQAQAEQEAERLRTEAA 643

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1916926375  267 AALNQTegvmeRLEQEIAELRRRD---AELEQL-SHAED 301
Cdd:NF041483   644 ADASAA-----RAEGENVAVRLRSeaaAEAERLkSEAQE 677

polarized growth protein Scy;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375  189 SAAER--TEKQKELGATQRKFQQRIQEREKELQDLRQAV-----------ESLTRSAQAAVEDSERIFTELIRSIERRRS 255
Cdd:NF041483   688 AAAERvgTEAAEALAAAQEEAARRRREAEETLGSARAEAdqererareqsEELLASARKRVEEAQAEAQRLVEEADRRAT 767

                           90       100       110
                   ....*....|....*....|....*....|..
gi 1916926375  256 EVKKLIRDQEKAALNQTEGVMERLEQEIAELR 287
Cdd:NF041483   768 ELVSAAEQTAQQVRDSVAGLQEQAEEEIAGLR 799

PRY/SPRY domain in tripartite motif-containing (TRIM) proteins, including TRIM14-like, TRIM16-like, TRIM25-like, TRIM47-like, TRIM65 and RNF135, and stonustoxin; 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 TRIM14, TRIM16 and TRIM25, TRIM47 as well as RING finger protein RNF135 and stonustoxin, a secreted poisonous protein of the stonefish Synanceja horrida. TRIM16 (also known as estrogen-responsive B box protein or EBBP) has E3 ubiquitin ligase activity. It is a regulator of keratinocyte differentiation and a tumor suppressor in retinoid-sensitive neuroblastoma. 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. TRIM47, also known as GOA (Gene overexpressed in astrocytoma protein) or RNF100 (RING finger protein 100), is highly expressed in kidney tubular cells, but low expressed in most tissue. It is overexpressed in astrocytoma tumor cells and plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. RNF135 ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Stonustoxin (STNX) is a hypotensive and lethal protein factor that also possesses other biological activities such as species-specific hemolysis (due to its ability to form pores in the cell membrane) and platelet aggregation, edema-induction, and endothelium-dependent vasorelaxation (mediated by the nitric oxide pathway and activation of potassium channels). 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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFnYWQQVLCREGL-SGRCYWEAEWSG-GGVYIAVSYKEISRKGr 462
Cdd:cd12891     1 LTLDPNTAHNNLALSGDLKTVTCSSENQHYPDSPERF-THSQVLSTQSFsSGRHYWEVEVSEsGGWSVGVAYPSIERKG- 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 463 sDDYWFGHNEKSWSLCCSASEYSFWYNNKKTETPAPTSPRIGVYLDHRAGTLSFYSVSDTMTLLYRVQTTFTQPLYPGFW 542
Cdd:cd12891    79 -DESRIGRNDKSWCLEWQDKSFSAWHNNEETPLPSVSSRRLGVYLDYEAGRLSFYELSDPIRHLHTFTATFTEPLHPAFW 157

                         170
                  ....*....|
gi 1916926375 543 LYRGSTVKLC 552
Cdd:cd12891   158 VLEGGWIRIK 167

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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGL-SGRCYWEAEWSG-GGVYIAVSYKEISRKGr 462
Cdd:cd12874     1 LTFDPDTAHLNLILSDDLRSVRVGDISQHPPEPPPRFFECWQVLGSQSFsSGRHYWEVDVQDdSSWYVGVTYKSLPRKG- 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 463 sDDYWFGHNEKSWSLCCSASEYSFWYNNKKTETPAPTSPRIGVYLDHRAGTLSFYSVSDTMTLLYRVQTTFTQPLYPGFW 542
Cdd:cd12874    80 -KMSNLGRNNGSWCLEWRENEFSAWHNNPETRLPVTPPRRLGVFLDCDGGSLSFYGVTDGVQLLYTFKAKFTEPLYPAFW 158

                         170
                  ....*....|
gi 1916926375 543 LYRGSTVKLC 552
Cdd:cd12874   159 LGEGSTLSIC 168

PRY/SPRY domain in tripartite motif-binding protein 7 (TRIM7)-like, including TRIM7, TRIM10, TRIM15, TRIM26, TRIM39, TRIM41; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several tripartite motif-containing (TRIM) proteins, including TRIM7 (also referred to as glycogenin-interacting protein, RING finger protein 90 or RNF90), TRIM10, TRIM15, TRIM26, TRIM39 and TRIM41. TRIM7 or GNIP interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. TRIM10 (also known as hematopoietic RING finger 1 (HERF1) or TRIM10/HERF1) plays a key role in definitive erythroid development; downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival. Antiviral activity of TRIM15 is dependent on the ability of its B-box to interact with the MLV Gag precursor protein; downregulation of TRIM15, along with TRIM11, enhances virus release suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells. Tripartite motif-containing 26 (TRIM26) function is as yet unknown; however, since it is localized in the human histocompatibility complex (MHC) class I region, TRIM26 may play a role in immune response although studies show no association between TRIM26 polymorphisms and the risk of aspirin-exacerbated respiratory disease. TRIM39 is a MOAP-1 (Modulator of Apoptosis)-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process. TRIM41 (also known as RING finger-interacting protein with C kinase or RINCK) functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGL-SGRCYWEAEWSGGGVY-IAVSYKEISRKGR 462
Cdd:cd12888     2 VTLDPDTAHPRLVLSEDRKSVRWGDTRQDLPDNPERFDTWPCVLGCEGFtSGRHYWEVEVGDGGGWaVGVARESVRRKGE 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 463 SDdywFGHNEKSWSLCCSASEYSfWYNNKKTETPAPTSPR-IGVYLDHRAGTLSFYSVsDTMTLLYrvqtTFTQPLYPG- 540
Cdd:cd12888    82 IS---FSPEEGIWAVGQWGGQYW-ALTSPETPLPLSEVPRrIRVYLDYEGGQVAFFDA-DNEAPIF----TFPPASFAGe 152

                         170
                  ....*....|....*..
gi 1916926375 541 -----FWLYRGSTVKLC 552
Cdd:cd12888   153 rifpwFWVGKGSQLKLC 169

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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREG-LSGRCYWEA--EWSGGGVYIAVSYKEISRKG 461
Cdd:cd13738     1 PTLEPDTLHPRLRLSDDRLTVSCGWLGTLGLCPPQRFDKLWQVLSRDSfFSGRHYWEVdlQEAGAGWWVGAAYPSIGRKG 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 462 RSDDYWFGHNEKSWSLCCSASEYSFWYNNKKTETPAPTSP-RIGVYLDHRAGTLSFYSVSDTMTLLYRVQTTFTQPLYPG 540
Cdd:cd13738    81 DSEAARLGWNRQSWCLKRYDLEYWAFHDGQRSRLRPEDDPdRLGVFLDYEAGILSFYDVTGGMTHLHTFRATFQEPLYPA 160

                  ....*...
gi 1916926375 541 FWLYRGST 548
Cdd:cd13738   161 LRLWEGSI 168

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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYwQQVLCREGLS-GRCYWEAEWSGGGVY-IAVSYKEISRK-- 460
Cdd:cd12902     1 PTFDLRSLSCSLEVSEDSRKVTVSHGPQAYAWSPDRFSI-SQVLCSQAFSsGQHYWEVDTRQCSHWaVGVASWEMSRDqm 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 461 -GRSDDYWFghneKSWSlccSASEYSFWYNNKKTETPAPTSPRIGVYLDHRAGTLSFYSVSDTMTLLYRVQTTFTQPLYP 539
Cdd:cd12902    80 lGRTMDSWC----IEWK---GTGQLSAWHMNKETVLGSDKPRVVGIWLDLEEGKLAFYSVANQERLLHECEVSASSPLHP 152

                  ....*
gi 1916926375 540 GFWLY 544
Cdd:cd12902   153 AFWLY 157

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 1916926375  11 EQFSCSICLDLLKDPVTIPCGHSYCMDCIKGCWDqDDHTGVYSCPQCRETFTSRPVLRRNTLLAEVVEK 79
Cdd:cd16597     4 EELTCSICLELFKDPVTLPCGHNFCGVCIEKTWD-SQHGSEYSCPQCRATFPRRPELHKNTVLRNIVEQ 71

butyrophilin subfamily member A1 and A2 (BTN1A and BTN2A); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of butyrophilin family 1A and 2A (BTN1A and BTN2A). BTNs belong to receptor glycoproteins of immunoglobulin (Ig) superfamily, characterized by the presence of extracellular Ig-like domains (IgV and/or IgC). BTN1A plays a role in the secretion, formation and stabilization of milk fat globules. The B30.2 domain of BTN1A1 binds the enzyme xanthine oxidoreductase (XOR) in order to participate in milk fat globule secretion; this interaction may lead to the production of reactive oxygen species, which have immunomodulatory and antimicrobial functions. Duplication events have led to three paralogs of BTN2A in primates: BTN2A1, BTN2A2, and BTN2A3. In humans, only BTN2A1 has been functionally characterized; it has been detected on epithelial cells and leukocytes, and identified as a novel ligand of dendritic cell-specific ICAM-3 grabbing nonintegrin (DCSIGN), a C-type lectin receptor that acts as an internalization receptor for HIV-1, HCV, and other pathogens. BTN2A2 mRNA has been shown to be expressed in circulating human immune cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 386 TLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGL-SGRCYWEAEWSGGGVY-IAVSYKEISRKGRs 463
Cdd:cd15819     5 TLDPDTAHPALILSEDGRSVTWGETRQDLPENPERFDSLPCVLGQEGFtSGRHYWEVEVGDRTSWdLGVCRDNVMRKGR- 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 464 ddywfghnekswslCCSASEYSFW----YNNK-------KTETPAPTSP-RIGVYLDHRAGTLSFYSVSDTMTLLYRVQT 531
Cdd:cd15819    84 --------------VTLSPENGFWairlYGNEywaltspETPLTLKEPPrRVGIFLDYEAGDVSFYNMTDGSHIYTFPQT 149

                         170
                  ....*....|..
gi 1916926375 532 TFTQPLYPGFWL 543
Cdd:cd15819   150 AFSGPLRPFFRL 161

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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGT--VKQPYPDHPERFNYWQQVLCREGL-SGRCYWEAEWSGGGVY-IAVSYKEISRK 460
Cdd:cd12904     1 LRFDERTVSPLLSLSEDRRTLTFSPkkARQSPPDDPERFDHWPNALASLSFsSGTHAWVVDVGKSCAYkVGVCYGSLERK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 461 GRSDDYWFGHNEKSWSLCCSASEYSFWYNNKKTETPAPTSP-RIGVYLDHRAGTLSFYSvSDTMTLLYRVQTTFTQPLYP 539
Cdd:cd12904    81 GSGNEARLGYNAFSWVFSRYDGEFSFSHNGQHVPLELLKCPaRVGVLLDWPSQELLFYD-PDSCTVLHSHREAFAAPLLP 159

                  ..
gi 1916926375 540 GF 541
Cdd:cd12904   160 VF 161

PRY/SPRY domain in tripartite motif-containing protein 35 (TRIM35); This PRY/SPRY domain is found at the C-terminus of the overall domain architecture of tripartite motif 35, TRIM35 (also known as hemopoietic lineage switch protein), which includes a RING finger domain (RING) and a B-box motif (BBOX). TRIM35 may play a role as a tumor suppressor and is implicated in the cell death mechanism.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 386 TLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGL-SGRCYWEAE------WsgggvYIAVSYKEIS 458
Cdd:cd12893     3 TLDPNTAHPWLSLSEDLTSVRYSSEKQQLPDNPERFDPYPCVLGSEGFtSGKHSWDVEvgdntsW-----MLGVAKESVQ 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 459 RKGrsddyWFGHNEKS--WSLCCSASEYSfwynnkKTETPAPTSP--------RIGVYLDHRAGTLSFYSvSDTMTLLYR 528
Cdd:cd12893    78 RKG-----KFTLSPESgfWTIGFSEGKYS------ARTSPEPRTPlrvkqkpqRIRVQLDWDRGKVSFSD-PDTNTHIHT 145

                         170       180
                  ....*....|....*....|....*
gi 1916926375 529 VQTTFTQPLYPGFWLYRGST-VKLC 552
Cdd:cd12893   146 FTHTFTERVFPYFYTGCKSEpLRIL 170

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 1916926375  10 QEQFSCSICLDLLKDPVTIPCGHSYCMDCIKGCWDQDDhtGVYSCPQCRETFTSRP 65
Cdd:cd16543     1 EDQLTCSICLDLLKDPVTIPCGHSFCMNCITLLWDRKQ--GVPSCPQCRESFPPRP 54

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 1916926375 385 LTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGLS-GRCYWEAEW---SGGGVYIAVSYKEISRK 460
Cdd:cd15826     2 VTLDPQTASGSLVLSEDRKSVRYTRQKQNLPDSPLRFDGLPAVLGSPGFSsGRHRWQVEVqlgDGGGCTVGVAGESVRRK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 461 GrsdDYWFGHNEKSWSLCCSASEysFWYNNK-KTETPAPTSP-RIGVYLDHRAGTLSFYSvSDTMTLLYRVQTTFTQPLY 538
Cdd:cd15826    82 G---EMGLSAEDGVWAVILSHQQ--CWASTSpGTDLPLSEIPrRVGVALDYEAGTVTLTN-AETQEPIFTFTASFSGKVF 155

                         170
                  ....*....|....
gi 1916926375 539 PGFWLY-RGSTVKL 551
Cdd:cd15826   156 PFFAVWkKGSRLTL 169

PRY/SPRY domain in tripartite motif-binding (TRIM) proteins TRIM50 and TRIM72; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several TRIM proteins, including TRIM72 and TRIM50. TRIM72 (also known as MG53) has been shown to perform a critical function in membrane repair following acute muscle injury by nucleating the assembly of the repair machinery at injury sites. It is expressed specifically in skeletal muscle and heart, and tethered to the plasma membrane and cytoplasmic vesicles via its interaction with phosphatidylserine. TRIM50, an E3 ubiquitin ligase, is deleted in Williams-Beuren (WBS) syndrome, a multi-system neurodevelopmental disorder caused by the deletion of contiguous genes at chromosome region 7q11.23.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 384 QLTLDPNTANTHLCLSEGNRAVTCGTVKQPYPDHPERFNYWQQVLCREGLS-GRCYWE------AEWSGGgvyiaVSYKE 456
Cdd:cd12897    13 SLTFDPATAHPLLVVSSGGTVVECGLQKQRRASQPERFDKSTCVVASQGFSeGEHYWEvvvgdkPRWALG-----VIKGT 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1916926375 457 ISRKGRSddywfgHNEKS---WSLCCSASEYSFWYNNKKTETPAPTS---PRIGVYLDHRAGTLSFYSVS--DTMTLLYR 528
Cdd:cd12897    88 ASRKGKL------HASPShgvWLIGLKEGKVYEAHGEPKEPRPLRVAgrpHRIGVYLSFEDGVLSFFDASdpDDLRTLYT 161

                         170       180
                  ....*....|....*....|..
gi 1916926375 529 VQTTFTQPLYPGF---WLYRGS 547
Cdd:cd12897   162 FQERFQGKLYPFFdvcWHDKGK 183