B-Box C-terminal domain; Coiled coil region C-terminal to (some) B-Box domains

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879    1 MVQQIQENSVEFEACLVAQCDALIDALNRRKAQLLARVNKEHEHKLKVVRDQISHCTVKLRQTTGLMEYCLEVIKENDPS 80
Cdd:smart00502  29 IIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKVLEQQLESLTQKQEKLSHAINFTEEALNSGDPT 108

                           90
                   ....*....|....*....
gi 1907089879   81 GFLQISDALIRRVHLTEDQ 99
Cdd:smart00502 109 ELLLSKKLIIERLQNLLKQ 127

B-Box C-terminal domain; Coiled coil region C-terminal to (some) B-Box domains

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879    1 MVQQIQENSVEFEACLVAQCDALIDALNRRKAQLLARVNKEHEHKLKVVRDQISHCTVKLRQTTGLMEYCLEVIKENDPS 80
Cdd:smart00502  29 IIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKVLEQQLESLTQKQEKLSHAINFTEEALNSGDPT 108

                           90
                   ....*....|....*....
gi 1907089879   81 GFLQISDALIRRVHLTEDQ 99
Cdd:smart00502 109 ELLLSKKLIIERLQNLLKQ 127

Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 153 THNNSATLSWKQPPLSTVAADGYILELDDGSGGQFREVYV--GKETMCTVDGLHFNSTYNARVKAFNKTGVSPYSKTLVL 230
Cdd:cd00063    12 VTSTSVTLSWTPPEDDGGPITGYVVEYREKGSGDWKEVEVtpGSETSYTLTGLKPGTEYEFRVRAVNGGGESPPSESVTV 91

                  ..
gi 1907089879 231 QT 232
Cdd:cd00063    92 TT 93

Fibronectin type 3 domain; One of three types of internal repeat within the plasma protein, fibronectin. The tenth fibronectin type III repeat contains a RGD cell recognition sequence in a flexible loop between 2 strands. Type III modules are present in both extracellular and intracellular proteins.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1907089879  153 THNNSATLSWKQPPLSTVAA--DGYILELDDGSGGQFREVYVGKETMCTVDGLHFNSTYNARVKAFNKTGVS 222
Cdd:smart00060  12 VTSTSVTLSWEPPPDDGITGyiVGYRVEYREEGSEWKEVNVTPSSTSYTLTGLKPGTEYEFRVRAVNGAGEG 83

Fibronectin type 3 domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 132 VQVKASSPVPATP-ILQLEEccTHNNSATLSWKQPplSTVAADGYILELDDGSGGQFREVY-VGKETMCTVDGLHFNSTY 209
Cdd:COG3401   318 VSVTTDLTPPAAPsGLTATA--VGSSSITLSWTAS--SDADVTGYNVYRSTSGGGTYTKIAeTVTTTSYTDTGLTPGTTY 393

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907089879 210 NARVKAFNKTGV-SPYSKTLVLQTSEGCNFETQSASYSqlvAWFAFDPGSAHSDIIFSNDNLTVTCSSYDD 279
Cdd:COG3401   394 YYKVTAVDAAGNeSAPSEEVSATTASAASGESLTASVD---AVPLTDVAGATAAASAASNPGVSAAVLADG 461

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 1907089879 252 FAFDPGSAHSDIIFSNDNLTVTCSSY--------------DDRVVLGKTGFSKGVHYWELTIDRYdnhPDPAFGVARIDV 317
Cdd:cd13734     1 FKLDPKTAHRKLRLSNDNLTVEYDPEgskdqaavlprrftGSPAVLGDVAISSGRHYWEVSVSRS---TSYRVGVAYKSA 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 318 MKDMMLGKDDKAWAITEGGIT----------------KGATIGVLLDLNRKTLTFFVNNEQQGPIAFENV-EGLFFPAVS 380
Cdd:cd13734    78 PRDEDLGKNSTSWCLSRDNNRytarhdgkvvdlrvtgHPARIGVLLDYDNGTLSFYDAESKQHLYTFHVDfEGPVCPAFA 157

                         170
                  ....*....|
gi 1907089879 381 LNrNVQVTLH 390
Cdd:cd13734   158 VW-NGSLTLH 166

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 255 DPGSAHSDIIFSNDNLTVT---CSSYDDRVVLGKTGFSKGVHYWELTIDrydnHP----DPAFGV----ARIDVMKDM-- 321
Cdd:cd12876     5 DERDKSPAVQLSDNNREVYfhpDYSCGTAAVRGTKPLTNGQHYWEIKMS----SPvygtDMMVGVgtkkADLHAYRYEfc 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907089879 322 -MLGKDDKAW------AITEGGITK---------GATIGVLLDLNRKTLTFFVNNEQQGpIAFENVEGL--FFPAVS 380
Cdd:cd12876    81 sLLGEDEESWglsykgLLWHDGQSRpytspfgnqGTIIGVHLDMWRGTLTFYKNGKPLG-VAFTGLNGVkpLYPMVS 156

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 1907089879 291 GVHYWELTIDRyDNHPDPAFGVAR--IDVMKDMMLGKDDKAWAI---------------TEGGITKGATIGVLLDLNRKT 353
Cdd:cd11709     1 GKWYWEVRVDS-GNGGLIQVGWATksFSLDGEGGVGDDEESWGYdgsrlrkghggssgpGGRPWKSGDVVGCLLDLDEGT 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1907089879 354 LTFFVNNEQQGpIAFENV---EGLFFPAVSLNRNVQVTLH 390
Cdd:cd11709    80 LSFSLNGKDLG-VAFTNLflkGGGLYPAVSLGSGQGVTIN 118

SPRY domain in Ash2; This SPRY domain is found at the C-terminus of Ash2 (absent, small, or homeotic discs 2) -like proteins, core components of all mixed-lineage leukemia (MLL) family histone methyltransferases. Ash2 is a member of the trithorax group of transcriptional regulators of the Hox genes. Recent studies show that the SPRY domain of Ash2 mediates the interaction with RbBP5 and has an important role in regulating the methyltransferase activity of MLL complexes. In yeast, Ash2 is involved in histone methylation and is required for the earliest stages of embryogenesis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 263 IIFSNDNLTVTCSS-YddRVVLGKTGFSKGVHYWELTIDRYDNHPDPA--FGVARIDVMKDMMLGKDDKAWAI------- 332
Cdd:cd12872     1 LKLSEDRLTVTGEKgY--RMARANHGVREGKWYFEVKILEGGGTETGHvrVGWSRREASLQAPVGYDKYSYAIrdkdgsk 78

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907089879 333 ---------TEGGITKGATIGVLLDLNRktLTFFVNNEQQGPiAFENV--EGLFFPAVSLNRNVQVTLHTGlpvPDFY 399
Cdd:cd12872    79 fhqsrgkpyGEPGFKEGDVIGFLITLPK--IEFFKNGKSQGV-AFEDIygTGGYYPAVSLYKGATVTINFG---PDFK 150

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 1907089879 254 FDPGSAHSDIIFSNDNLTVTCSSYDDRV-----------VLGKTGFSKGVHYWELTIdryDNHPDPAFGVA--RIDVMKD 320
Cdd:cd12891     3 LDPNTAHNNLALSGDLKTVTCSSENQHYpdsperfthsqVLSTQSFSSGRHYWEVEV---SESGGWSVGVAypSIERKGD 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907089879 321 M-MLGKDDKAWAITEGGITKGA---------------TIGVLLDLNRKTLTFF 357
Cdd:cd12891    80 EsRIGRNDKSWCLEWQDKSFSAwhnneetplpsvssrRLGVYLDYEAGRLSFY 132

Fibronectin type III domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907089879 155 NNSATLSWKQPPLSTVAADGYILEL-DDGSGGQFREVYVGK-ETMCTVDGLHFNSTYNARVKAFNKTGVSPYS 225
Cdd:pfam00041  13 STSLTVSWTPPPDGNGPITGYEVEYrPKNSGEPWNEITVPGtTTSVTLTGLKPGTEYEVRVQAVNGGGEGPPS 85

Fibronectin type 3 domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 132 VQVKASSPVPATPI-LQLEEccTHNNSATLSWkqPPLSTVAADGYILELDDGSGGQFREVYVGKETMCTVDGLHFNSTYN 210
Cdd:COG3401   224 VSVTTPTTPPSAPTgLTATA--DTPGSVTLSW--DPVTESDATGYRVYRSNSGDGPFTKVATVTTTSYTDTGLTNGTTYY 299

                          90       100
                  ....*....|....*....|....
gi 1907089879 211 ARVKAFNKTGV-SPYSKTLVLQTS 233
Cdd:COG3401   300 YRVTAVDAAGNeSAPSNVVSVTTD 323

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 1907089879 254 FDPGSAHSDIIFSNDNLTVTCSS-------YDDRV----VLGKTGFSKGVHYWELtidRYDNHPDPAFGVARIDVMKDMM 322
Cdd:cd12902     3 FDLRSLSCSLEVSEDSRKVTVSHgpqayawSPDRFsisqVLCSQAFSSGQHYWEV---DTRQCSHWAVGVASWEMSRDQM 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907089879 323 LGKDDKAWAI----------------TEGGITKGATIGVLLDLNRKTLTFF-VNNEQ 362
Cdd:cd12902    80 LGRTMDSWCIewkgtgqlsawhmnkeTVLGSDKPRVVGIWLDLEEGKLAFYsVANQE 136

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 1907089879 254 FDPGSAHSDIIFSNDNLTVTCSS-----------YD-DRVVLGKTGFSKGVHYWELTIDRYDNHpdpAFGVARIDVMK-- 319
Cdd:cd12888     4 LDPDTAHPRLVLSEDRKSVRWGDtrqdlpdnperFDtWPCVLGCEGFTSGRHYWEVEVGDGGGW---AVGVARESVRRkg 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907089879 320 DMMLGKDDKAWAI-TEGGITKGAT--------------IGVLLDLNRKTLTFFvNNEQQGPIaFEnveglfFPAVSLNR 383
Cdd:cd12888    81 EISFSPEEGIWAVgQWGGQYWALTspetplplsevprrIRVYLDYEGGQVAFF-DADNEAPI-FT------FPPASFAG 151

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 310 FGVARIDVMKDMMLGKDDKAWAIT--------EGGIT------KGATIGVLLDLNRKTLTFFVNNE-----QQGPIAFEN 370
Cdd:cd12878    30 VGWARPGFRPDLELGSDDLSYAFDgflarkwhQGSESfgkqwqPGDVVGCMLDLVDRTISFTLNGEllidsSGSEVAFKD 109

                          90       100
                  ....*....|....*....|....
gi 1907089879 371 VEGL--FFPAVSLNRNVQVTLHTG 392
Cdd:cd12878   110 IEIGegFVPACSLGVGQKGRLNLG 133

SPRY domain at N-terminus of ring finger protein 123; This SPRY domain is found at the N-terminus of RING finger protein 123 domain (also known as E3 ubiquitin-protein ligase RNF123). The ring finger domain motif is present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RNF123 displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor p27 (Kip1).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907089879 340 GATIGVLLDLNRKTLTFFVNNEQQGpIAFENVEGL----FFPAVSLNRNVQVTLHTG 392
Cdd:cd12882    73 GDVIGCCIDLDKGTISFYRNGRSLG-VAFDNVRRGpglaYFPAVSLSFGERLELNFG 128

Ret finger protein-like (RFPL), includes RFP1, 2, 3, 4; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of RFPL protein family, which includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development; human RFPL1 decreases cell number through its RFPL-defining motif (RDM) and SPRY domains. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 254 FDPGSAHSDIIFSNDNLTVTCSS-----------YDDRV-VLGKTGFSKGVHYWELTIDR---YDnhpdpaFGVARIDV- 317
Cdd:cd15821     8 LDVDTANNYLIISEDLRSVRCGCfrqnrkelaerFDDALcVLGSPRFTSGRHYWEVDVGTsteWD------LGVCRESVn 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907089879 318 -MKDMMLGKDDKAWAIT--EGGI----TKGAT----------IGVLLDLNRKTLTFF 357
Cdd:cd15821    82 rQGPIELSPEHGFWTVSlrDGSVffasTVPLTvlwvnprlhrVGIFLDMEMGTISFY 138

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907089879 254 FDPGSAHSDIIFSNDNLTVTCSSYDDRV------------VLGKTGFSKGVHYWELTIdryDNHPDPAFGV 312
Cdd:cd12897    16 FDPATAHPLLVVSSGGTVVECGLQKQRRasqperfdkstcVVASQGFSEGEHYWEVVV---GDKPRWALGV 83

PRY/SPRY domain in tripartite motif-binding protein 62 (TRIM62); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM62. It is also called DEAR1 ductal epithelium (associated RING chromosome 1) and is involved in the morphogenesis of the mammary gland; loss of TRIM62 gene expression in breast is associated with increased risk of recurrence in early-onset breast cancer and thus, making TRIM62 a predictive biomarker. Non-small cell lung cancer lesions show a step-wise loss of TRIM62 levels during disease progression, indicating that it may play a role in the evolution of lung cancer. Decreased levels of TRIM62 also represent an independent adverse prognostic factor in AML.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907089879 250 AWFAFDPGSAHSDIIFSNDNLTVTCSS------------YDDRV-VLGKTGFSKGVHYWELTI 299
Cdd:cd13744    12 AALTLDPVTAHQRLILSDDCTIVAYGNlhpqplqdspkrFDVEVsVLGSEGFSGGVHYWEVVV 74

PRY/SPRY domain in tripartite motif-containing domain 65 (TRIM65); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM65 proteins (composed of RING/B-box/coiled-coil core and also known as RBCC proteins). The SPRY/PRY combination is a possible component of immune defense. This protein family has not been characterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 254 FDPGSAHSDIIFSNDNLTVT------------CSSYDDRVVLGKTGFSKGVHYWELTIdrydNHPDPAFGVA-------R 314
Cdd:cd12896    14 FDPRTANKYLELSRQNRRAKhgrsaargvpasPGSFELWQVQCTQSFQHGHHYWEVEV----SSHSVTLGVTypglprhK 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 315 IDVMKDmMLGKDDKAWA--ITEGGIT-------------KGATIGVLLDLNRKTLTFFVNNEQQGPI-AFENV--EGLfF 376
Cdd:cd12896    90 QGGHKD-NIGRNPCSWGlqIQEDSLQawhngraqklqgvSYRLLGVDLDLEAGTLTFYGLEPGTQRLhTFHAIftQPL-Y 167

                         170
                  ....*....|...
gi 1907089879 377 PAVSLNRNVQVTL 389
Cdd:cd12896   168 PVFWLLEGRTLTL 180

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 1907089879 255 DPGSAHSDIIFSNDNLTVTCSSY------------DDRVVLGKTGFSKGVHYWELTIdryDNHPDPAFGVARIDVMKDMM 322
Cdd:cd15819     7 DPDTAHPALILSEDGRSVTWGETrqdlpenperfdSLPCVLGQEGFTSGRHYWEVEV---GDRTSWDLGVCRDNVMRKGR 83

                          90
                  ....*....|..
gi 1907089879 323 --LGKDDKAWAI 332
Cdd:cd15819    84 vtLSPENGFWAI 95

PRY/SPRY domain in tripartite motif-binding protein 72 (TRIM72); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM72. Muscle-specific TRIM72 (also known as Mitsugumin 53 or 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. TRIM72 interacts with dysferlin, a sarcolemmal protein whose deficiency causes Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B); this coordination plays an important role in the repair of sarcolemma damage.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907089879 253 AFDPGSAHSDIIFSNDNLTVTCS------SYDD-------RVVLGKTGFSKGVHYWELTIdryDNHPDPAFGV 312
Cdd:cd13742    15 TFDPDTAHPYLVVSSDGKRVECAdqkqavSSDDpnrfdkaNCVVSHQSFSEGEHYWEVIV---GDKPRWALGV 84

SPRY domain 1 (SPRY1) of ryanodine receptor (RyR); This SPRY domain is the first of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this first SPRY domain of the RyRs.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907089879 337 ITKGATIGVLLDLNRKTLTFFVN-NEQQGpiAFE--NVEGLFFPAVSLNRNVQV 387
Cdd:cd12877    95 LKKGDVVGCCLDLSVPSISFRVNgRPVQG--MFEnfNLDGMFFPVMSFSAGVSC 146

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907089879 254 FDPGSAHSDIIFSNDNLTVTCS-----------SYDD-RVVLGKTGFSKGVHYWEL 297
Cdd:cd13738     3 LEPDTLHPRLRLSDDRLTVSCGwlgtlglcppqRFDKlWQVLSRDSFFSGRHYWEV 58

PRY/SPRY domain in tripartite motif-binding protein 7 (TRIM7); 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 7 (TRIM7), also referred to as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90). TRIM7 or GNIP interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. The GNIP gene encodes at least four distinct isoforms of GNIP, of which three (GNIP1, GNIP2, and GNIP3) have the B30.2 domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 255 DPGSAHSDIIFSNDNLTV------------TCSSYDDRVVLGKTGFSKGVHYWELTIDRYDNHpdpAFGVARIDVMKDMM 322
Cdd:cd13740     5 DPDSANPRLILSLDLKSVrlgeraqdlpnhPCRFDTNTRVLASCGFSSGRHHWEVEVGSKDGW---AFGVARESVRRKGL 81

                          90
                  ....*....|....*.
gi 1907089879 323 --LGKDDKAWAITEGG 336
Cdd:cd13740    82 tpFTPEEGVWALQLNG 97

PRY/SPRY domain in tripartite motif-binding protein 69 (TRIM69), also known as RING finger protein 36 (RNF36); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM69, which is also known as RING finger protein 36 (RNF36) or testis-specific ring finger (Trif). TRIM69 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It is a novel testis E3 ubiquitin ligase that may function to ubiquitinate its particular substrates during spermatogenesis. In humans, TRIM69 localizes in the cytoplasm and nucleus, and requires an intact RING finger domain to function. The mouse ortholog of this gene is specifically expressed in germ cells at the round spermatid stages during spermatogenesis and, when overexpressed, induces apoptosis. TRIM69 has been shown to be a novel regulator of mitotic spindle assembly in tumor cells; it associates with spindle poles and promotes centrosomal clustering, and is therefore essential for formation of a bipolar spindle.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907089879 255 DPGSAHSDIIFSNDnltVTCSSYDDR---------------VVLGKTGFSKGVHYWELTI 299
Cdd:cd15818    18 DPKTAHPNLILSED---LTCVWHGDTkqmlpdnperfdssvAVLGSEGFTSGKHYWEVEV 74

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 1907089879 255 DPGSAHSDIIFSNDNLTV-------TCSSYDDR-----VVLGKTGFSKGVHYWELTIdryDNHPDPAFGVAridvmKDMM 322
Cdd:cd15817     5 DPETAHPNLIVSEDRKAVryrrmkpNCPYDPRRftvypAVLGSEGFDSGRHFWEVEV---GGKGEWILGVC-----KDSL 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1907089879 323 LGK-------DDKAWAITEGG---------------ITKGATIGVLLDLNRKTLTFFVNNEQ 362
Cdd:cd15817    77 PRNaqdppspLGGCWQIGRYMsgyvasgpkttqllpVVKPSRIGIFLDYELGEVSFYNMNDR 138

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1907089879 255 DPGSAHSDIIFSNDNLTVTC-----SSYD-------DRVVLGKTGFSKGVHYWELtidRYDNHPDPAFGVAR 314
Cdd:cd15829    24 DPETAHPNLLVSEDKKCVTFtkkkqRVPDspkrftvNPVVLGFPGFHSGRHFWEV---EVGDKPEWAVGVCK 92

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 1907089879 254 FDPGSAHSDIIFSNDNLTVTCS----SYDD--------RVVLGKTGFSkGVHYWEL--------------TIDRYDNHPD 307
Cdd:cd16040    13 LDPNTAHRNLSLSEGNRKVTRVkeeqPYPDhperfdywPQVLCREGLS-GRCYWEVewsgggvdiavaykGISRKGDGDD 91

                  ....
gi 1907089879 308 PAFG 311
Cdd:cd16040    92 SRFG 95