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 1059433488 270 FRLDASTSHQNLRVDDLSVEWDAMGGKV-QDIKAREKDGKGRTASPINSPARGtPSPKRMPSGRGGRDRFTAESYTVLGD 348
Cdd:cd12901     1 FKLDASSSHQNLKVEDLSVEWDATGGKVlQKIKGRENDGRSRTASPRNSSARC-QSPKRMPSARGGRDRFTAESYTVLGD 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1059433488 349 TLIDGGEHYWEVRYEPDSKAFGVGVAYRSLGRFEQLGKTAASWCLHVNNWLQAS 402
Cdd:cd12901    80 TLIDGGQHYWEVRAQKDSKAFSVGVAYRSLGKFDQLGKTNASWCLHVNNWLQNS 133

coiled-coil (CC) domain of Drosophila brain tumor (brat) and similar proteins; This family contains the coiled-coil (CC) region of Drosophila brain tumor (Brat), a translational repressor that belongs to the tripartite motif (TRIM) protein superfamily. TRIM proteins play important roles in various cellular processes and are involved in many diseases which consists of two B-box domains and a coiled-coil (CC) domain at the N-terminal region, and an NHL domain at the C-terminus. Brat localizes at the basal cortex during asymmetric division of Drosophila neuroblasts by directly interacting with the scaffolding protein Miranda (Mira), which it does through the CC-NHL domain tandem, indicating that the function of the Brat CC domain is to assemble Brat-NHL in dimeric form which is necessary for Mira binding. Brat CC forms an elongated antiparallel dimer similar to its other TRIM protein counterparts, but the overall length of Brat CC dimer is shorter than the TRIMs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488    4 QREALRKIIKTLAVKNEEIQSFIYSLKQMLLNVEANSAKVQEDLEAEFQSLFSLLEELKEGMLMKIKQDRASRTYELQNQ 83
Cdd:smart00502   1 QREALEELLTKLRKKAAELEDALKQLISIIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKVLEQQ 80

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1059433488   84 LAACTRALESSEELLETANQTLQAMDSEDFPQAAKQI 120
Cdd:smart00502  81 LESLTQKQEKLSHAINFTEEALNSGDPTELLLSKKLI 117

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488 270 FRLDASTSHQNLRVDDLSVEWDAMGGKV-QDIKAREKDGKGRTASPINSPARGtPSPKRMPSGRGGRDRFTAESYTVLGD 348
Cdd:cd12901     1 FKLDASSSHQNLKVEDLSVEWDATGGKVlQKIKGRENDGRSRTASPRNSSARC-QSPKRMPSARGGRDRFTAESYTVLGD 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1059433488 349 TLIDGGEHYWEVRYEPDSKAFGVGVAYRSLGRFEQLGKTAASWCLHVNNWLQAS 402
Cdd:cd12901    80 TLIDGGQHYWEVRAQKDSKAFSVGVAYRSLGKFDQLGKTNASWCLHVNNWLQNS 133

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488    4 QREALRKIIKTLAVKNEEIQSFIYSLKQMLLNVEANSAKVQEDLEAEFQSLFSLLEELKEGMLMKIKQDRASRTYELQNQ 83
Cdd:smart00502   1 QREALEELLTKLRKKAAELEDALKQLISIIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKVLEQQ 80

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1059433488   84 LAACTRALESSEELLETANQTLQAMDSEDFPQAAKQI 120
Cdd:smart00502  81 LESLTQKQEKLSHAINFTEEALNSGDPTELLLSKKLI 117

Fibronectin type 3 domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488 154 QMLQALKFLPVPSAPViDLAESLVADNCVTLVWRmPDEDSKIDHYVLeYRRTNfegpprlkEDQPWMVIEGIRQTEYTLT 233
Cdd:COG3401   222 NEVSVTTPTTPPSAPT-GLTATADTPGSVTLSWD-PVTESDATGYRV-YRSNS--------GDGPFTKVATVTTTSYTDT 290

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1059433488 234 GLKFDMKYmNFRVKACNKA-VAGEFSEPVTLETPAFmfrldASTSHQNLRV-----DDLSVEWDA 292
Cdd:COG3401   291 GLTNGTTY-YYRVTAVDAAgNESAPSNVVSVTTDLT-----PPAAPSGLTAtavgsSSITLSWTA 349

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1059433488  354 GEHYWEVRYEpDSKAFGVGVAYRS--LGRFEQLGKTAASWCLH---VNNWLQASCPSTMPapnkccTLSRPGSHSRCCL 427
Cdd:smart00449   2 GRHYFEVEIG-DGGHWRVGVATKSvpRGYFALLGEDKGSWGYDgdgGKKYHNSTGPEYGL------PLQEPGDVIGCFL 73

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488 270 FRLDASTSHQNLRVDDLSVEWDAMGGKV-QDIKAREKDGKGRTASPINSPARGtPSPKRMPSGRGGRDRFTAESYTVLGD 348
Cdd:cd12901     1 FKLDASSSHQNLKVEDLSVEWDATGGKVlQKIKGRENDGRSRTASPRNSSARC-QSPKRMPSARGGRDRFTAESYTVLGD 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1059433488 349 TLIDGGEHYWEVRYEPDSKAFGVGVAYRSLGRFEQLGKTAASWCLHVNNWLQAS 402
Cdd:cd12901    80 TLIDGGQHYWEVRAQKDSKAFSVGVAYRSLGKFDQLGKTNASWCLHVNNWLQNS 133

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 1059433488 165 PSAPViDLAESLVADNCVTLVWRMPDED-SKIDHYVLEYRRTNfegpprlkeDQPWMVIEG--IRQTEYTLTGLKFDMKY 241
Cdd:cd00063     1 PSPPT-NLRVTDVTSTSVTLSWTPPEDDgGPITGYVVEYREKG---------SGDWKEVEVtpGSETSYTLTGLKPGTEY 70

                          90       100
                  ....*....|....*....|....
gi 1059433488 242 mNFRVKACNKAVAGEFSEPVTLET 265
Cdd:cd00063    71 -EFRVRAVNGGGESPPSESVTVTT 93

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 1059433488 272 LDASTSHQNLRV--DDLSVEWDAMGGKvqdikarekdgkgrtaspinspargtpspkrmpsgRGGRDRFTAESYTVLGDT 349
Cdd:cd12874     3 FDPDTAHLNLILsdDLRSVRVGDISQH-----------------------------------PPEPPPRFFECWQVLGSQ 47

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1059433488 350 LIDGGEHYWEVRYEpDSKAFGVGVAYRSLGRF---EQLGKTAASWCLHVNN 397
Cdd:cd12874    48 SFSSGRHYWEVDVQ-DDSSWYVGVTYKSLPRKgkmSNLGRNNGSWCLEWRE 97

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1059433488 330 SGRGGRDRFTAESytVLGDTLIDGGEHYWEVRYEpDSKAFGVGVAYRSL---GRFEQLGKTAASWCLHVNN 397
Cdd:cd12891    29 HYPDSPERFTHSQ--VLSTQSFSSGRHYWEVEVS-ESGGWSVGVAYPSIerkGDESRIGRNDKSWCLEWQD 96

PRY/SPRY domain of tripartite motif-binding protein 1 (TRIM1) or MID2; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM1 (also known as MID2 or midline 2). 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. MID2 and MID1 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 MID1 have shown to cause Opitz syndrome, a disorder causing congenital anomalies such as cleft lip and palate as well as heart defects.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488 270 FRLDASTSHQNLRVDDlsvewdamggkvqDIKAREKDgkgrtaspiNSPARGTPSPKRMpSGRGgrdrftaeSYTVLGDT 349
Cdd:cd13739     1 FKLDPKMAHKKLKISN-------------DGLQMEKD---------ESSLKKSHTPERF-SGTG--------CYGAAGNI 49

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1059433488 350 LIDGGEHYWEVRYEpDSKAFGVGVAYRSLGRFEQLGKTAASWCL 393
Cdd:cd13739    50 FIDSGCHYWEVVVG-SSTWYAIGIAYKSAPKNEWIGKNSSSWVF 92

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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1059433488 336 DRFTAESytVLGDTLIDGGEHYWEVRYEpDSKAFGVGVAYRSLGRFEQLGKTAASWCL 393
Cdd:cd12902    35 DRFSISQ--VLCSQAFSSGQHYWEVDTR-QCSHWAVGVASWEMSRDQMLGRTMDSWCI 89

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 1059433488 345 VLGDTLIDGGEHYWEVRYEPDSKAFGVGVAYRSLGR-----FEQLGKTAASWCL 393
Cdd:cd13738    43 VLSRDSFFSGRHYWEVDLQEAGAGWWVGAAYPSIGRkgdseAARLGWNRQSWCL 96

PRY/SPRY domain in tripartite motif-containing protein 76 (TRIM76)-like; This domain is similar to the distinct PRY/SPRY subdomain found at the C-terminus of TRIM76, a Class I TRIM protein. TRIM76 (also known as cardiomyopathy-associated protein 5 or CMYA5 or myospryn or SPRYD2) is a muscle-specific member of the TRIM superfamily, but lacks the RING domain. It has been suggested that TRIM76 is involved in two distinct processes, protein kinase A signaling and vesicular trafficking.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1059433488 345 VLGDTLIDGGEHYWEVRYEPDSKaFGVGVAYRSLGRFEQLGKTAASWCL 393
Cdd:cd12899    47 VMGSLIPVRGKHYWEVEVDEQTE-YRVGVAFEDTQRNGYLGANNTSWCM 94

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1059433488 337 RFTAESyTVLGDTLIDGGEHYWEVryEPDSKAF-GVGVAYRSLGR---FEQLGKTAASWCLH-VNNWLQA---SCPSTMP 408
Cdd:cd13736    36 RFTYCS-QVLGLHCFKQGIHYWEV--ELQKNNFcGVGICYGSMDRqgpESRLGRNSESWCVEwFNVKISAwhnNVEKTLP 112

                  ...
gi 1059433488 409 APN 411
Cdd:cd13736   113 STK 115

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1059433488  354 GEHYWEVRYEpDSKAFGVGVAYRS--LGRFEQLGKTAASWCLH---VNNWLQASCPSTMPapnkccTLSRPGSHSRCCL 427
Cdd:smart00449   2 GRHYFEVEIG-DGGHWRVGVATKSvpRGYFALLGEDKGSWGYDgdgGKKYHNSTGPEYGL------PLQEPGDVIGCFL 73

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
                  ....*....|....*....|....*....|....*....|....*
gi 1059433488 354 GEHYWEVryEPDSKAFGVGVAYRSLGRFEQ-----LGKTAASWCL 393
Cdd:cd16040    61 GRCYWEV--EWSGGGVDIAVAYKGISRKGDgddsrFGYNDKSWSL 103