C-terminal deadenylase domain of nocturnin and related domains; This subfamily contains the C-terminal catalytic domain of the deadenylase, nocturnin, and related domains. Nocturnin is a poly(A)-specific 3' exonuclease that specifically degrades the 3' poly(A) tail of RNA in a process known as deadenylation. This nuclease activity is manganese dependent. Nocturnin is expressed in the cytoplasm of Xenopus laevis retinal photoreceptor cells in a rhythmic fashion, and it has been proposed that it participates in posttranscriptional regulation of the circadian clock or its outputs, and that the mRNA target(s) of this deadenylase are circadian clock-related. In mouse, the nocturnin gene, mNoc, is expressed in a circadian pattern in a range of tissues including retina, spleen, heart, kidney, and liver. It is highly expressed in bone-marrow stromal cells, adipocytes and hepatocytes. In mammals, nocturnin plays a role in regulating mesenchymal stem-cell lineage allocation, perhaps through regulating PPAR-gamma (peroxisome proliferator-activated receptor-gamma) nuclear translocation. This subfamily belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  32 NILApiyKRLS-HKDQSLRESDNRAYWLGRNHRIIDWLLYERSSIICLQEFwvgnEELVNLYEKRLGDAGYLSYKLG--- 107
Cdd:cd09096    6 NILA---QALGeGKDGFVRCPCEALKWEERKYLILEEILTYDPDILCLQEV----DHYKDTLQPLLSRLGYQGTFFPkpd 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 108 ------RTNN--RGLLTAVHKDYFRVVNSRDLLFNDCGDRVAQllhVELVPPYSQYDAHQEVLIVNTHLlfPHDSTLSIV 179
Cdd:cd09096   79 spclyiENNNgpDGCALFFRKDRFELVNTEKIRLSAMTLKTNQ---VAIACTLRCKETGREICLAVTHL--KARTGWERL 153

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 186531948 180 RLQQVYKILQYVESYQKEVNlspMPIILCGDWNGSKRGHVYKFLRSQGFvsSYDTAHRYTDSDAHK 245
Cdd:cd09096  154 RSEQGKDLLQNLQSFIEGAK---IPLIICGDFNAEPTEPVYKTFSNSSL--NLNSAYKLLSADGQS 214

C-terminal deadenylase domain of nocturnin and related domains; This subfamily contains the C-terminal catalytic domain of the deadenylase, nocturnin, and related domains. Nocturnin is a poly(A)-specific 3' exonuclease that specifically degrades the 3' poly(A) tail of RNA in a process known as deadenylation. This nuclease activity is manganese dependent. Nocturnin is expressed in the cytoplasm of Xenopus laevis retinal photoreceptor cells in a rhythmic fashion, and it has been proposed that it participates in posttranscriptional regulation of the circadian clock or its outputs, and that the mRNA target(s) of this deadenylase are circadian clock-related. In mouse, the nocturnin gene, mNoc, is expressed in a circadian pattern in a range of tissues including retina, spleen, heart, kidney, and liver. It is highly expressed in bone-marrow stromal cells, adipocytes and hepatocytes. In mammals, nocturnin plays a role in regulating mesenchymal stem-cell lineage allocation, perhaps through regulating PPAR-gamma (peroxisome proliferator-activated receptor-gamma) nuclear translocation. This subfamily belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  32 NILApiyKRLS-HKDQSLRESDNRAYWLGRNHRIIDWLLYERSSIICLQEFwvgnEELVNLYEKRLGDAGYLSYKLG--- 107
Cdd:cd09096    6 NILA---QALGeGKDGFVRCPCEALKWEERKYLILEEILTYDPDILCLQEV----DHYKDTLQPLLSRLGYQGTFFPkpd 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 108 ------RTNN--RGLLTAVHKDYFRVVNSRDLLFNDCGDRVAQllhVELVPPYSQYDAHQEVLIVNTHLlfPHDSTLSIV 179
Cdd:cd09096   79 spclyiENNNgpDGCALFFRKDRFELVNTEKIRLSAMTLKTNQ---VAIACTLRCKETGREICLAVTHL--KARTGWERL 153

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 186531948 180 RLQQVYKILQYVESYQKEVNlspMPIILCGDWNGSKRGHVYKFLRSQGFvsSYDTAHRYTDSDAHK 245
Cdd:cd09096  154 RSEQGKDLLQNLQSFIEGAK---IPLIICGDFNAEPTEPVYKTFSNSSL--NLNSAYKLLSADGQS 214

C-terminal deadenylase domain of CCR4 and related domains; This subfamily contains the C-terminal catalytic domain of the deadenylases, Saccharomyces cerevisiae Ccr4p and two vertebrate homologs (CCR4a and CCR4b), and related domains. CCR4 belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. CCR4 is the major deadenylase subunit of the CCR4-NOT transcription complex, which contains two deadenylase subunits and several noncatalytic subunits. The other deadenylase subunit, Caf1 (called Pop2 in yeast), is a DEDD-type protein and does not belong in this superfamily. Saccharomyces cerevisiae CCR4 (or Ccr4p) is a 3'-5' poly(A) RNA and ssDNA exonuclease. It is the catalytic subunit of the yeast mRNA deadenylase (Ccr4p/Pop2p/Not complex). This complex participates in various ways in mRNA metabolism, including transcription initiation and elongation, and mRNA degradation. Ccr4p degrades both poly(A) and single-stranded DNA. There are two vertebrate homologs of Ccr4p, CCR4a (also called CCR4-NOT transcription complex subunit 6 or CNOT6) and CCR4b (also called CNOT6-like or CNOT6L), which independently associate with other components to form distinct CCR4-NOT multisubunit complexes. The nuclease domain of CNOT6 and CNOT6L exhibits Mg2+-dependent deadenylase activity, with specificity for poly (A) RNA as substrate. CCR4a is a component of P-bodies and is necessary for foci formation. CCR4b regulates p27/Kip1 mRNA levels, thereby influencing cell cycle progression. They both contribute to the prevention of cell death by regulating insulin-like growth factor-binding protein 5.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  57 WLGRNHRIIDWLLYERSSIICLQEfwVGNEELVNLYEKRLGDAGYLSYKLGRTNNR-----------GLLTAVHKDYFRV 125
Cdd:cd09097   27 WDYRKQNILKEILSYNADILCLQE--VETDQYEDFFLPELKQHGYDGVFKPKSRAKtmseaerkhvdGCAIFFKTSKFKL 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 126 VNSRDLLFNDCG-------------------DRVAQLLHVELVPPYSQYDAHQEVLIVNTHLLFPHDstLSIVRLQQVYK 186
Cdd:cd09097  105 VEKHLIEFNQLAmanadaegsedmlnrvmtkDNIALIVVLEARETSYEGNKGQLLIVANTHIHWDPE--FSDVKLVQTMM 182

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|
gi 186531948 187 ILQYVESYQKEVNLSP------MPIILCGDWNGSKRGHVYKFLrSQGFVS 230
Cdd:cd09097  183 LLEELEKIAEKFSRYPyedsadIPLVVCGDFNSLPDSGVYELL-SNGSVS 231

Neutral sphingomyelinases (nSMase) catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine; Sphingomyelinases (SMase) are phosphodiesterases that catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Eukaryotic SMases have been classified according to their pH optima and are known as acid SMase, alkaline SMase, and neutral SMase (nSMase). Eukaryotic proteins in this family are nSMases, and are activated by a variety of stress-inducing agents such as cytokines or UV radiation. Ceramides and other metabolic derivatives, including sphingosine, are lipid "second messenger" molecules that participate in the regulation of stress-induced cellular responses, including cell death, adhesion, differentiation, and proliferation. Bacterial neutral SMases, which also belong to this domain family, are secreted proteins that act as membrane-damaging virulence factors. They promote colonization of the host tissue. This family belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  75 IICLQE-FwvGNEELVNLYEKRLGDAGYLSYKLGRTNNR--------GLLTAVHkdyFRVVNSRDLLFNDCG--DRVAQ- 142
Cdd:cd09078   39 VVVLQEvF--DARARKRLLNGLKKEYPYQTDVVGRSPSGwssklvdgGVVILSR---YPIVEKDQYIFPNGCgaDCLAAk 113

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 143 -LLHVELVPPYSQYdahqeVLIVNTHLLFPHDSTLS-IVRLQQVYKILQYVESYQKEVNlspMPIILCGDWN---GSKRG 217
Cdd:cd09078  114 gVLYAKINKGGTKV-----YHVFGTHLQASDGSCLDrAVRQKQLDELRAFIEEKNIPDN---EPVIIAGDFNvdkRSSRD 185

                 ....*....
gi 186531948 218 HVYKFLRSQ 226
Cdd:cd09078  186 EYDDMLEQL 194

Exonuclease-Endonuclease-Phosphatase (EEP) domain superfamily; This large superfamily includes the catalytic domain (exonuclease/endonuclease/phosphatase or EEP domain) of a diverse set of proteins including the ExoIII family of apurinic/apyrimidinic (AP) endonucleases, inositol polyphosphate 5-phosphatases (INPP5), neutral sphingomyelinases (nSMases), deadenylases (such as the vertebrate circadian-clock regulated nocturnin), bacterial cytolethal distending toxin B (CdtB), deoxyribonuclease 1 (DNase1), the endonuclease domain of the non-LTR retrotransposon LINE-1, and related domains. These diverse enzymes share a common catalytic mechanism of cleaving phosphodiester bonds; their substrates range from nucleic acids to phospholipids and perhaps proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  60 RNHRIIDWLLYERSSIICLQEfwVGNEELVNLYEKRLGDAGYLSYKLGRTNnrglltavHKDYFRVVnsrdLLFNDCGDR 139
Cdd:cd08372   14 RASGIARWVRELDPDIVCLQE--VKDSQYSAVALNQLLPEGYHQYQSGPSR--------KEGYEGVA----ILSKTPKFK 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 140 VAQLLHVELVPPYSQ--------YDAH-QEVLIVNTHLlfPHDSTLSIVRLQQVYKILQYVESYQKEVNLspmPIILCGD 210
Cdd:cd08372   80 IVEKHQYKFGEGDSGerravvvkFDVHdKELCVVNAHL--QAGGTRADVRDAQLKEVLEFLKRLRQPNSA---PVVICGD 154

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 186531948 211 WNGSKRGHVYKFLRSQGF--------VSSYDTAHRYT 239
Cdd:cd08372  155 FNVRPSEVDSENPSSMLRlfvalnlvDSFETLPHAYT 191

Exonuclease-Endonuclease-Phosphatase (EEP) domain superfamily; uncharacterized family 2; This family of uncharacterized proteins belongs to a superfamily that includes the catalytic domain (exonuclease/endonuclease/phosphatase, EEP, domain) of a diverse set of proteins including the ExoIII family of apurinic/apyrimidinic (AP) endonucleases, inositol polyphosphate 5-phosphatases (INPP5), neutral sphingomyelinases (nSMases), deadenylases (such as the vertebrate circadian-clock regulated nocturnin), bacterial cytolethal distending toxin B (CdtB), deoxyribonuclease 1 (DNase1), the endonuclease domain of the non-LTR retrotransposon LINE-1, and related domains. These diverse enzymes share a common catalytic mechanism of cleaving phosphodiester bonds; their substrates range from nucleic acids to phospholipids and perhaps, proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948  62 HRIIDWLLYERSSIICLQEFWvgNEELVNLYEKRLGDAGY----LSYKlGRTNNRGLLTAVHkdyFRVVNSRDLLFNDCG 137
Cdd:cd09084   19 DKILDFIKKQDPDILCLQEYY--GSEGDKDDDLRLLLKGYpyyyVVYK-SDSGGTGLAIFSK---YPILNSGSIDFPNTN 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186531948 138 DRVAQllhVELVPPysqydaHQEVLIVNTHL----LFPHDSTLS---IVRLQQVYKILQ-----------YVESYQKEVN 199
Cdd:cd09084   93 NNAIF---ADIRVG------GDTIRVYNVHLesfrITPSDKELYkeeKKAKELSRNLLRklaeafkrraaQADLLAADIA 163

                        170       180       190
                 ....*....|....*....|....*....|....*
gi 186531948 200 LSPMPIILCGDWNGSKRGHVYKFLRSQ---GFVSS 231
Cdd:cd09084  164 ASPYPVIVCGDFNDTPASYVYRTLKKGltdAFVEA 198