DEDDh 3'-5' exonuclease domain of three prime repair exonuclease (TREX)1, TREX2, and similar proteins; Three prime repair exonuclease (TREX)1 and TREX2 are closely related DEDDh-type DnaQ-like 3'-5' exonucleases. They contain three conserved sequence motifs known as ExoI, II, and III, with a specific Hx(4)D conserved pattern at ExoIII. These motifs contain four conserved acidic residues that participate in coordination of divalent metal ions required for catalysis. Both proteins play a role in the metabolism and clearance of DNA. TREX1 is the major 3'-5' exonuclease activity detected in mammalian cells. Mutations in the human TREX1 gene can cause Aicardi-Goutieres syndrome (AGS), which is characterized by perturbed innate immunity and presents itself as a severe neurological disease. TREX1 degrades ssDNA generated by aberrant replication intermediates to prevent checkpoint activation and autoimmune disease. There are distinct structural differences between TREX1 and TREX2 that point to different biological roles for these proteins. The main difference is the presence of about 70 amino acids at the C-terminus of TREX1. In addition, TREX1 has a nonrepetitive proline-rich region that is not present in the TREX2 protein. Furthermore, TREX2 contains a conserved DNA binding loop positioned adjacent to the active site that has a sequence distinct from the corresponding loop in TREX1. Truncations in the C-terminus of human TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), a neurovascular syndrome featuring a progressive loss of visual acuity combined with a variable neurological picture.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  14 LIFLDLEATGLPYS-QPKITELCLLAVHRHALENSSMSEGqpppvpKPPRVVDKLSLCIAPGKPCSSGASEITGLTTAGL 92
Cdd:cd06136   1 FVFLDLETTGLPKHnRPEITELCLVAVHRDHLLNTSRDKP------ALPRVLDKLSLCFNPGRAISPGASEITGLSNDLL 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  93 EAhgRQRFNDNLATLLQVFLQRQPQPCCLVAHNGDRYDFPLLQAELASLSVISPlDGTFCVDSIAALKTLEQasspsehg 172
Cdd:cd06136  75 EH--KAPFDSDTANLIKLFLRRQPKPICLVAHNGNRFDFPILRSELERLGTKLP-DDILCVDSLPAFRELDQ-------- 143

                       170       180       190
                ....*....|....*....|....*....|....*....
gi 68163427 173 prksySLGSIYTRLYGQAPTDSHTAEGDVLALLSICQWK 211
Cdd:cd06136 144 -----SLGSLYKRLFGQEPKNSHTAEGDVLALLKCALHK 177

DEDDh 3'-5' exonuclease domain of three prime repair exonuclease (TREX)1, TREX2, and similar proteins; Three prime repair exonuclease (TREX)1 and TREX2 are closely related DEDDh-type DnaQ-like 3'-5' exonucleases. They contain three conserved sequence motifs known as ExoI, II, and III, with a specific Hx(4)D conserved pattern at ExoIII. These motifs contain four conserved acidic residues that participate in coordination of divalent metal ions required for catalysis. Both proteins play a role in the metabolism and clearance of DNA. TREX1 is the major 3'-5' exonuclease activity detected in mammalian cells. Mutations in the human TREX1 gene can cause Aicardi-Goutieres syndrome (AGS), which is characterized by perturbed innate immunity and presents itself as a severe neurological disease. TREX1 degrades ssDNA generated by aberrant replication intermediates to prevent checkpoint activation and autoimmune disease. There are distinct structural differences between TREX1 and TREX2 that point to different biological roles for these proteins. The main difference is the presence of about 70 amino acids at the C-terminus of TREX1. In addition, TREX1 has a nonrepetitive proline-rich region that is not present in the TREX2 protein. Furthermore, TREX2 contains a conserved DNA binding loop positioned adjacent to the active site that has a sequence distinct from the corresponding loop in TREX1. Truncations in the C-terminus of human TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), a neurovascular syndrome featuring a progressive loss of visual acuity combined with a variable neurological picture.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  14 LIFLDLEATGLPYS-QPKITELCLLAVHRHALENSSMSEGqpppvpKPPRVVDKLSLCIAPGKPCSSGASEITGLTTAGL 92
Cdd:cd06136   1 FVFLDLETTGLPKHnRPEITELCLVAVHRDHLLNTSRDKP------ALPRVLDKLSLCFNPGRAISPGASEITGLSNDLL 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  93 EAhgRQRFNDNLATLLQVFLQRQPQPCCLVAHNGDRYDFPLLQAELASLSVISPlDGTFCVDSIAALKTLEQasspsehg 172
Cdd:cd06136  75 EH--KAPFDSDTANLIKLFLRRQPKPICLVAHNGNRFDFPILRSELERLGTKLP-DDILCVDSLPAFRELDQ-------- 143

                       170       180       190
                ....*....|....*....|....*....|....*....
gi 68163427 173 prksySLGSIYTRLYGQAPTDSHTAEGDVLALLSICQWK 211
Cdd:cd06136 144 -----SLGSLYKRLFGQEPKNSHTAEGDVLALLKCALHK 177

exonuclease domain in DNA-polymerase alpha and epsilon chain, ribonuclease T and other exonucleases;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427     13 TLIFLDLEATGLPYSQPKITELCLLAVHRHALEnssmsegqpppvpkpprvvDKLSLCIAPGKPCSSGASEITGLTTAGL 92
Cdd:smart00479   1 TLVVIDCETTGLDPGKDEIIEIAAVDVDGGEII-------------------EVFDTYVKPDRPITDYATEIHGITPEML 61

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427     93 EahGRQRFNDNLATLLQVFlqrqpQPCCLVAHNGDRYDFPLLQAELASLSVISPLDGtFCVDSIAalktLEQASSPSehg 172
Cdd:smart00479  62 D--DAPTFEEVLEELLEFL-----RGRILVAGNSAHFDLRFLKLEHPRLGIKQPPKL-PVIDTLK----LARATNPG--- 126

                          170       180       190
                   ....*....|....*....|....*....|....*....
gi 68163427    173 pRKSYSLGSIYTRLYGQAPTDSHTAEGDVLALLSICQWK 211
Cdd:smart00479 127 -LPKYSLKKLAKRLLLEVIQRAHRALDDARATAKLFKKL 164

DEDDh 3'-5' exonuclease domain of three prime repair exonuclease (TREX)1, TREX2, and similar proteins; Three prime repair exonuclease (TREX)1 and TREX2 are closely related DEDDh-type DnaQ-like 3'-5' exonucleases. They contain three conserved sequence motifs known as ExoI, II, and III, with a specific Hx(4)D conserved pattern at ExoIII. These motifs contain four conserved acidic residues that participate in coordination of divalent metal ions required for catalysis. Both proteins play a role in the metabolism and clearance of DNA. TREX1 is the major 3'-5' exonuclease activity detected in mammalian cells. Mutations in the human TREX1 gene can cause Aicardi-Goutieres syndrome (AGS), which is characterized by perturbed innate immunity and presents itself as a severe neurological disease. TREX1 degrades ssDNA generated by aberrant replication intermediates to prevent checkpoint activation and autoimmune disease. There are distinct structural differences between TREX1 and TREX2 that point to different biological roles for these proteins. The main difference is the presence of about 70 amino acids at the C-terminus of TREX1. In addition, TREX1 has a nonrepetitive proline-rich region that is not present in the TREX2 protein. Furthermore, TREX2 contains a conserved DNA binding loop positioned adjacent to the active site that has a sequence distinct from the corresponding loop in TREX1. Truncations in the C-terminus of human TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), a neurovascular syndrome featuring a progressive loss of visual acuity combined with a variable neurological picture.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  14 LIFLDLEATGLPYS-QPKITELCLLAVHRHALENSSMSEGqpppvpKPPRVVDKLSLCIAPGKPCSSGASEITGLTTAGL 92
Cdd:cd06136   1 FVFLDLETTGLPKHnRPEITELCLVAVHRDHLLNTSRDKP------ALPRVLDKLSLCFNPGRAISPGASEITGLSNDLL 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  93 EAhgRQRFNDNLATLLQVFLQRQPQPCCLVAHNGDRYDFPLLQAELASLSVISPlDGTFCVDSIAALKTLEQasspsehg 172
Cdd:cd06136  75 EH--KAPFDSDTANLIKLFLRRQPKPICLVAHNGNRFDFPILRSELERLGTKLP-DDILCVDSLPAFRELDQ-------- 143

                       170       180       190
                ....*....|....*....|....*....|....*....
gi 68163427 173 prksySLGSIYTRLYGQAPTDSHTAEGDVLALLSICQWK 211
Cdd:cd06136 144 -----SLGSLYKRLFGQEPKNSHTAEGDVLALLKCALHK 177

DNA polymerase III, epsilon subunit or related 3'-5' exonuclease [Replication, recombination and repair];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  14 LIFLDLEATGLPYSQPKITELCLLAVHRHALEnssmsegqpppvpkpprvvDKLSLCIAPGKPCSSGASEITGLTTAGLE 93
Cdd:COG0847   2 FVVLDTETTGLDPAKDRIIEIGAVKVDDGRIV-------------------ETFHTLVNPERPIPPEATAIHGITDEDVA 62

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  94 ahGRQRFNDNLATLLQvFLQRQPqpccLVAHNGdRYDFPLLQAELASLSVISPLDGTFCVDSIAALKtleqasspseHGP 173
Cdd:COG0847  63 --DAPPFAEVLPELLE-FLGGAV----LVAHNA-AFDLGFLNAELRRAGLPLPPFPVLDTLRLARRL----------LPG 124

                       170       180       190
                ....*....|....*....|....*....|.
gi 68163427 174 RKSYSLGSIYTRlYGQAPTDSHTAEGDVLAL 204
Cdd:COG0847 125 LPSYSLDALCER-LGIPFDERHRALADAEAT 154

DnaQ-like (or DEDD) 3'-5' exonuclease domain superfamily; The DnaQ-like exonuclease superfamily is a structurally conserved group of 3'-5' exonucleases, which catalyze the excision of nucleoside monophosphates at the DNA or RNA termini in the 3'-5' direction. It is also called the DEDD superfamily, after the four invariant acidic residues present in the catalytic site of its members. The superfamily consists of DNA- and RNA-processing enzymes such as the proofreading domains of DNA polymerases, other DNA exonucleases, RNase D, RNase T, Oligoribonuclease and RNA exonucleases (REX). The DnaQ-like exonuclease domain contains three conserved sequence motifs termed ExoI, ExoII and ExoIII, which are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis. The conservation patterns of the three motifs may vary among different subfamilies. DnaQ-like exonucleases are classified as DEDDy or DEDDh exonucleases depending on the variation of motif III as YX(3)D or HX(4)D, respectively. The significance of the motif differences is still unclear. Almost all RNase families in this superfamily are present only in eukaryotes and bacteria, but not in archaea, suggesting a later origin, which in some cases are accompanied by horizontal gene transfer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427  15 IFLDLEATGLPYSQPKITELCLLAVHrhalenssmsegqpppvpkpprVVDKLSLCIAPgkpcssgaseitglttaglea 94
Cdd:cd06125   1 IAIDTEATGLDGAVHEIIEIALADVN----------------------PEDTAVIDLKD--------------------- 37

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 68163427  95 hgrqrfndnlatllqvFLQRQPqPCCLVAHNGdRYDFPLLQAELASLSVISPLDGTFCVDSIAA 158
Cdd:cd06125  38 ----------------ILRDKP-LAILVGHNG-SFDLPFLNNRCAELGLKYPLLAGSWIDTIKL 83

DNA polymerase III subunit epsilon; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427    7 PHGHMQTLIFLDLEATGLPYSQPKITELCLLAVHRHALENSSmsegqpppvpkpprvvdkLSLCIAPGKPCSSGASEITG 86
Cdd:PRK07942   1 MSWHPGPLAAFDLETTGVDPETARIVTAALVVVDADGEVVES------------------REWLADPGVEIPEEASAVHG 62

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 68163427   87 LTTAGLEAHGR--QRFNDNLATLLQVFLQR-QPqpccLVAHNGdRYDFPLLQAELASLSVISPLDGTfCVDSIaalkTLE 163
Cdd:PRK07942  63 ITTEYARAHGRpaAEVLAEIADALREAWARgVP----VVVFNA-PYDLTVLDRELRRHGLPSLVPGP-VIDPY----VID 132

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 68163427  164 QASSPSEHGPRKsysLGSIYTRlYGQAPTDSHTAEGDVLA 203
Cdd:PRK07942 133 KAVDRYRKGKRT---LTALCEH-YGVRLDNAHEATADALA 168