macrodomain, Af1521-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. The macrodomains in this family show similarity to Af1521, a protein from Archaeoglobus fulgidus containing a stand-alone macrodomain. Af1521 binds ADP-ribose and exhibits phosphatase activity toward ADP-ribose-1"-monophosphate (Appr-1"-p). Also included in this family are the N-terminal (or first) macrodomains of BAL (B-aggressive lymphoma) proteins which contain multiple macrodomains, such as the first macrodomain of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  817 GVKLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIVKEGGVVLPGNAVISKAGKLPCHHVIHA 896
Cdd:cd02907     1 GIKVSVYKGDITKEKVDAIVNAANERLKHGGGVAGAISKAGGPEIQEECDKYIKKNGKLRVGEVVVTSAGKLPCKYVIHA 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 755553843  897 VGPRWKGDKVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCVANIVSAIKEhFQHKRDTHTLKKIYL 975
Cdd:cd02907    81 VGPRWSGGSKEECEDLLYKAVLNSLEEAEELKATSIAIPAISSGIFGFPLDLCAEAIVEAIKD-FSESNSSSSLKEIRL 158

macrodomain, B-aggressive lymphoma (BAL)-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. Members of this family show similarity to BAL (B-aggressive lymphoma) proteins, which contain one to three macrodomains. Most BAL family macrodomains belong to this family except for the most N-terminal domain in multiple-domain containing proteins. This family includes the second and third macrodomains of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1027 PEGLRIRLVEEGVQNATTHAIVNSISPDlKLNKGPLSQAFLEKAGPKLQEELtrSGQGVSVDVGTILQTSGCNLNSRHVF 1106
Cdd:cd02903     5 IGGITVQLVKGDITKEKTDVIVNSVSSD-LLLKGGVSKAILKAAGPELQDEC--ANQGKQPASGDVIVTSGGNLPCKYVY 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1107 HVVPPPWKSNNsawsLKIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLIISEVLKFSSRNQLKTLQEVQF 1186
Cdd:cd02903    82 HVVLPHYNPGN----EKTLKDIVRKCLEKAENYKMSSISFPAIGTGNLGFPKDVVAEIMIDEVLKFSSKNPSSSLKEVRF 157

                         170       180
                  ....*....|....*....|
gi 755553843 1187 LLHPKdhENIQAFSDEFDKR 1206
Cdd:cd02903   158 VIFPP--ETLQAFSDELAKR 175

RNA recognition motif 1 in vertebrate poly [ADP-ribose] polymerase 14 (PARP-14); This subfamily corresponds to the RRM1 of PARP-14, also termed aggressive lymphoma protein 2, a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs. It is expressed in B lymphocytes and interacts with the IL-4-induced transcription factor Stat6. It plays a fundamental role in the regulation of IL-4-induced B-cell protection against apoptosis after irradiation or growth factor withdrawal. It mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. PARP-14 acts as a transcriptional switch for Stat6-dependent gene activation. In the presence of IL-4, PARP-14 activates transcription by facilitating the binding of Stat6 to the promoter and release of HDACs from the promoter with an IL-4 signal. In contrast, in the absence of a signal, PARP-14 acts as a transcriptional repressor by recruiting HDACs. Moreover, the absence of PARP-14 protects against Myc-induced developmental block and lymphoma. Thus, PARP-14 may play an important role in Myc-induced oncogenesis. Research indicates that PARP-14 is also a binding partner with phosphoglucose isomerase (PGI)/ autocrine motility factor (AMF). It can inhibit PGI/AMF ubiquitination, thus contributing to its stabilization and secretion. PARP-14 contains two N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), three tandem macro domains, and C-terminal region with sequence homology to PARP catalytic domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843    6 SFPLLVEGSWGPDPPKNLINKLQVYFQSRKKSGGGECEVVPEPGNPARFRVLFSPEDgegreVRQNVLERGNHELvWQEK 85
Cdd:cd12300     1 PFPLLVEGDWDPSPPKKLKNKLEKYFQSKKRSGGGECTVETEGPSPQTARVSFVNEE-----VRERVLEKKEHEI-LQGE 74

                  ....*..
gi 755553843   86 GTFKLTV 92
Cdd:cd12300    75 GTVRLTV 81

macrodomain, Af1521-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. The macrodomains in this family show similarity to Af1521, a protein from Archaeoglobus fulgidus containing a stand-alone macrodomain. Af1521 binds ADP-ribose and exhibits phosphatase activity toward ADP-ribose-1"-monophosphate (Appr-1"-p). Also included in this family are the N-terminal (or first) macrodomains of BAL (B-aggressive lymphoma) proteins which contain multiple macrodomains, such as the first macrodomain of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  817 GVKLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIVKEGGVVLPGNAVISKAGKLPCHHVIHA 896
Cdd:cd02907     1 GIKVSVYKGDITKEKVDAIVNAANERLKHGGGVAGAISKAGGPEIQEECDKYIKKNGKLRVGEVVVTSAGKLPCKYVIHA 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 755553843  897 VGPRWKGDKVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCVANIVSAIKEhFQHKRDTHTLKKIYL 975
Cdd:cd02907    81 VGPRWSGGSKEECEDLLYKAVLNSLEEAEELKATSIAIPAISSGIFGFPLDLCAEAIVEAIKD-FSESNSSSSLKEIRL 158

macrodomain, B-aggressive lymphoma (BAL)-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. Members of this family show similarity to BAL (B-aggressive lymphoma) proteins, which contain one to three macrodomains. Most BAL family macrodomains belong to this family except for the most N-terminal domain in multiple-domain containing proteins. This family includes the second and third macrodomains of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1027 PEGLRIRLVEEGVQNATTHAIVNSISPDlKLNKGPLSQAFLEKAGPKLQEELtrSGQGVSVDVGTILQTSGCNLNSRHVF 1106
Cdd:cd02903     5 IGGITVQLVKGDITKEKTDVIVNSVSSD-LLLKGGVSKAILKAAGPELQDEC--ANQGKQPASGDVIVTSGGNLPCKYVY 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1107 HVVPPPWKSNNsawsLKIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLIISEVLKFSSRNQLKTLQEVQF 1186
Cdd:cd02903    82 HVVLPHYNPGN----EKTLKDIVRKCLEKAENYKMSSISFPAIGTGNLGFPKDVVAEIMIDEVLKFSSKNPSSSLKEVRF 157

                         170       180
                  ....*....|....*....|
gi 755553843 1187 LLHPKdhENIQAFSDEFDKR 1206
Cdd:cd02903   158 VIFPP--ETLQAFSDELAKR 175

ADP-ribose-binding protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  817 GVKLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIVKEGGVVLPGNAVISKAGKLPCHHVIHA 896
Cdd:PRK00431    2 GMRIEVVQGDITELEVDAIVNAANSSLLGGGGVDGAIHRAAGPEILEECRELRQQQGPCPTGEAVITSAGRLPAKYVIHT 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  897 VGPRWkGDKVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCVANIVSAIKEHFQHKRdthTLKKIYLV 976
Cdd:PRK00431   82 VGPVW-RGGEDNEAELLASAYRNSLRLAAELGLRSIAFPAISTGVYGYPLEDAARIAVKTVREFLTRHK---SPEEVYFV 157

                         170
                  ....*....|....*
gi 755553843  977 GLPAKVARAFAEAVK 991
Cdd:PRK00431  158 CYDEEAYRLYERLLT 172

Macro domain; The Macro or A1pp domain is a module of about 180 amino acids which can bind ADP-ribose (an NAD metabolite) or related ligands. Binding to ADP-ribose could be either covalent or non-covalent: in certain cases it is believed to bind non-covalently; while in other cases (such as Aprataxin) it appears to bind both non-covalently through a zinc finger motif, and covalently through a separate region of the protein. This domain is found in a number of otherwise unrelated proteins. It is found at the C-terminus of the macro-H2A histone protein 4 and also in the non-structural proteins of several types of ssRNA viruses such as NSP3 from alpha-viruses and coronaviruses. This domain is also found on its own in a family of proteins from bacteria, archaebacteria and eukaryotes. The 3D structure of the SARS-CoV Macro domain has a mixed alpha/beta fold consisting of a central seven-stranded twisted mixed beta sheet sandwiched between two alpha helices on one face, and three on the other. The final alpha-helix, located on the edge of the central beta-sheet, forms the C terminus of the protein. The crystal structure of AF1521 (a Macro domain-only protein from Archaeoglobus fulgidus) has also been reported and compared with other Macro domain containing proteins. Several Macro domain only proteins are shorter than AF1521, and appear to lack either the first strand of the beta-sheet or the C-terminal helix 5. Well conserved residues form a hydrophobic cleft and cluster around the AF1521-ADP-ribose binding site.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843   836 VNAANENLKHISGLAQALSKAAGPELQTECDQIVKegGVVLPGNAVISKAGKLPCHHVIHAVGPRWKGDKVLECVSLLKK 915
Cdd:pfam01661    1 VNAANSRLLGGGGVAGAIHRAAGPELLEECRELKK--GGCPTGEAVVTPGGNLPAKYVIHTVGPTWRHGGSHGEEELLES 78

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 755553843   916 VVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCV 950
Cdd:pfam01661   79 CYRNALALAEELGIKSIAFPAISTGIYGFPWEEAA 113

RNA recognition motif 1 in vertebrate poly [ADP-ribose] polymerase 14 (PARP-14); This subfamily corresponds to the RRM1 of PARP-14, also termed aggressive lymphoma protein 2, a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs. It is expressed in B lymphocytes and interacts with the IL-4-induced transcription factor Stat6. It plays a fundamental role in the regulation of IL-4-induced B-cell protection against apoptosis after irradiation or growth factor withdrawal. It mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. PARP-14 acts as a transcriptional switch for Stat6-dependent gene activation. In the presence of IL-4, PARP-14 activates transcription by facilitating the binding of Stat6 to the promoter and release of HDACs from the promoter with an IL-4 signal. In contrast, in the absence of a signal, PARP-14 acts as a transcriptional repressor by recruiting HDACs. Moreover, the absence of PARP-14 protects against Myc-induced developmental block and lymphoma. Thus, PARP-14 may play an important role in Myc-induced oncogenesis. Research indicates that PARP-14 is also a binding partner with phosphoglucose isomerase (PGI)/ autocrine motility factor (AMF). It can inhibit PGI/AMF ubiquitination, thus contributing to its stabilization and secretion. PARP-14 contains two N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), three tandem macro domains, and C-terminal region with sequence homology to PARP catalytic domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843    6 SFPLLVEGSWGPDPPKNLINKLQVYFQSRKKSGGGECEVVPEPGNPARFRVLFSPEDgegreVRQNVLERGNHELvWQEK 85
Cdd:cd12300     1 PFPLLVEGDWDPSPPKKLKNKLEKYFQSKKRSGGGECTVETEGPSPQTARVSFVNEE-----VRERVLEKKEHEI-LQGE 74

                  ....*..
gi 755553843   86 GTFKLTV 92
Cdd:cd12300    75 GTVRLTV 81

Poly(ADP-ribose) polymerase catalytic domain; Poly(ADP-ribose) polymerase catalyzes the covalent attachment of ADP-ribose units from NAD+ to itself and to a limited number of other DNA binding proteins, which decreases their affinity for DNA. Poly(ADP-ribose) polymerase is a regulatory component induced by DNA damage. The carboxyl-terminal region is the most highly conserved region of the protein. Experiments have shown that a carboxyl 40 kDa fragment is still catalytically active.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  1649 EYNMVASAFRQT-----CSNFFIEKIERIQNPALWRRYQAYKKsmdekngnVRNEKHLFHGTEASSLPQLNSNGF--NRS 1721
Cdd:pfam00644    3 EYQIIEKYFLSThdpthGYPLFILEIFRVQRDGEWERFQPKKK--------LRNRRLLWHGSRLTNFLGILSQGLriAPP 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  1722 YAGKNATAYGKGTYFAVKASYSAcdTYSRPD-TNGRKYMYYVRVLTGN------------------YTNG--------NA 1774
Cdd:pfam00644   75 EAPVTGYMFGKGIYFADDASKSA--NYCPPSeAHGNGLMLLSEVALGDmnelkkadyaeklppgkhSVKGlgktapesFV 152

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*...
gi 755553843  1775 SLIVPPSRDPQnaADLYDTVtdnDKNPSIFVVFYDNQTYPEYLITFRQ 1822
Cdd:pfam00644  153 DLDGVPLGKLV--ATGYDSS---VLLYNEYVVYNVNQVRPKYLLEVKF 195

Appr-1"-p processing enzyme; Function determined by Martzen et al. Extended family detected by reciprocal PSI-BLAST searches (unpublished results, and Pehrson _ Fuji).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843   1245 FQVATGNIIKEVADVIVNSTTLTFDLKSGVSKAILEGAGQNVEQE-CSLLAKQSN-HG-YIVTGGGLLQCKNIIHVVGGN 1321
Cdd:smart00506    2 LKVVKGDITKPRADAIVNAANSDGAHGGGVAGAIARAAGKALSKEeVRKLAGGECpVGtAVVTEGGNLPAKYVIHAVGPR 81

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|..
gi 755553843   1322 DVKKSVSC----------VLEECEQRNYSSICLPAIGTGNAQQDPNVVAKAI 1363
Cdd:smart00506   82 ASGHSKEGfellenayrnCLELAIELGITSVALPLIGTGIYGVPKDRSAQAL 133

Appr-1"-p processing enzyme; Function determined by Martzen et al. Extended family detected by reciprocal PSI-BLAST searches (unpublished results, and Pehrson _ Fuji).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843   1031 RIRLVEEGVQNATTHAIVNSISPDLKLNKGpLSQAFLEKAGPKLQEELTRSGQGVSVDVGTILQTSGCNLNSRHVFHVVP 1110
Cdd:smart00506    1 ILKVVKGDITKPRADAIVNAANSDGAHGGG-VAGAIARAAGKALSKEEVRKLAGGECPVGTAVVTEGGNLPAKYVIHAVG 79

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|....*
gi 755553843   1111 PPWkSNNSAWSLKIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLI 1165
Cdd:smart00506   80 PRA-SGHSKEGFELLENAYRNCLELAIELGITSVALPLIGTGIYGVPKDRSAQAL 133

ADP-ribose-binding protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1046 AIVNSISPDLkLNKGPLSQAFLEKAGPKLQEE--LTRSGQGvSVDVGTILQTSGCNLNSRHVFHVVPPPWK---SNNSAw 1120
Cdd:PRK00431   19 AIVNAANSSL-LGGGGVDGAIHRAAGPEILEEcrELRQQQG-PCPTGEAVITSAGRLPAKYVIHTVGPVWRggeDNEAE- 95

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1121 slkIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLIISEVLKFSSRnqLKTLQEVQFLLHpkDHENIQAFS 1200
Cdd:PRK00431   96 ---LLASAYRNSLRLAAELGLRSIAFPAISTGVYGYPLEDAARIAVKTVREFLTR--HKSPEEVYFVCY--DEEAYRLYE 168

                  ....*.
gi 755553843 1201 DEFDKR 1206
Cdd:PRK00431  169 RLLTQQ 174

Macro domain; The Macro or A1pp domain is a module of about 180 amino acids which can bind ADP-ribose (an NAD metabolite) or related ligands. Binding to ADP-ribose could be either covalent or non-covalent: in certain cases it is believed to bind non-covalently; while in other cases (such as Aprataxin) it appears to bind both non-covalently through a zinc finger motif, and covalently through a separate region of the protein. This domain is found in a number of otherwise unrelated proteins. It is found at the C-terminus of the macro-H2A histone protein 4 and also in the non-structural proteins of several types of ssRNA viruses such as NSP3 from alpha-viruses and coronaviruses. This domain is also found on its own in a family of proteins from bacteria, archaebacteria and eukaryotes. The 3D structure of the SARS-CoV Macro domain has a mixed alpha/beta fold consisting of a central seven-stranded twisted mixed beta sheet sandwiched between two alpha helices on one face, and three on the other. The final alpha-helix, located on the edge of the central beta-sheet, forms the C terminus of the protein. The crystal structure of AF1521 (a Macro domain-only protein from Archaeoglobus fulgidus) has also been reported and compared with other Macro domain containing proteins. Several Macro domain only proteins are shorter than AF1521, and appear to lack either the first strand of the beta-sheet or the C-terminal helix 5. Well conserved residues form a hydrophobic cleft and cluster around the AF1521-ADP-ribose binding site.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  1261 VNSTTLTFDLKSGVSKAILEGAGQNVEQECSLLAKQSN-HGYI-VTGGGLLQCKNIIHVVG--------GNDVKKSVSC- 1329
Cdd:pfam01661    1 VNAANSRLLGGGGVAGAIHRAAGPELLEECRELKKGGCpTGEAvVTPGGNLPAKYVIHTVGptwrhggsHGEEELLESCy 80

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 755553843  1330 --VLEECEQRNYSSICLPAIGTGNAQQDPNVVAKAI 1363
Cdd:pfam01661   81 rnALALAEELGIKSIAFPAISTGIYGFPWEEAARIA 116

macrodomain, Af1521-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. The macrodomains in this family show similarity to Af1521, a protein from Archaeoglobus fulgidus containing a stand-alone macrodomain. Af1521 binds ADP-ribose and exhibits phosphatase activity toward ADP-ribose-1"-monophosphate (Appr-1"-p). Also included in this family are the N-terminal (or first) macrodomains of BAL (B-aggressive lymphoma) proteins which contain multiple macrodomains, such as the first macrodomain of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  817 GVKLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIVKEGGVVLPGNAVISKAGKLPCHHVIHA 896
Cdd:cd02907     1 GIKVSVYKGDITKEKVDAIVNAANERLKHGGGVAGAISKAGGPEIQEECDKYIKKNGKLRVGEVVVTSAGKLPCKYVIHA 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 755553843  897 VGPRWKGDKVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCVANIVSAIKEhFQHKRDTHTLKKIYL 975
Cdd:cd02907    81 VGPRWSGGSKEECEDLLYKAVLNSLEEAEELKATSIAIPAISSGIFGFPLDLCAEAIVEAIKD-FSESNSSSSLKEIRL 158

macrodomain, B-aggressive lymphoma (BAL)-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. Members of this family show similarity to BAL (B-aggressive lymphoma) proteins, which contain one to three macrodomains. Most BAL family macrodomains belong to this family except for the most N-terminal domain in multiple-domain containing proteins. This family includes the second and third macrodomains of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1027 PEGLRIRLVEEGVQNATTHAIVNSISPDlKLNKGPLSQAFLEKAGPKLQEELtrSGQGVSVDVGTILQTSGCNLNSRHVF 1106
Cdd:cd02903     5 IGGITVQLVKGDITKEKTDVIVNSVSSD-LLLKGGVSKAILKAAGPELQDEC--ANQGKQPASGDVIVTSGGNLPCKYVY 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1107 HVVPPPWKSNNsawsLKIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLIISEVLKFSSRNQLKTLQEVQF 1186
Cdd:cd02903    82 HVVLPHYNPGN----EKTLKDIVRKCLEKAENYKMSSISFPAIGTGNLGFPKDVVAEIMIDEVLKFSSKNPSSSLKEVRF 157

                         170       180
                  ....*....|....*....|
gi 755553843 1187 LLHPKdhENIQAFSDEFDKR 1206
Cdd:cd02903   158 VIFPP--ETLQAFSDELAKR 175

ADP-ribose-binding protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  817 GVKLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIVKEGGVVLPGNAVISKAGKLPCHHVIHA 896
Cdd:PRK00431    2 GMRIEVVQGDITELEVDAIVNAANSSLLGGGGVDGAIHRAAGPEILEECRELRQQQGPCPTGEAVITSAGRLPAKYVIHT 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  897 VGPRWkGDKVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELCVANIVSAIKEHFQHKRdthTLKKIYLV 976
Cdd:PRK00431   82 VGPVW-RGGEDNEAELLASAYRNSLRLAAELGLRSIAFPAISTGVYGYPLEDAARIAVKTVREFLTRHK---SPEEVYFV 157

                         170
                  ....*....|....*
gi 755553843  977 GLPAKVARAFAEAVK 991
Cdd:PRK00431  158 CYDEEAYRLYERLLT 172

macrodomain, O-acetyl-ADP-ribose (OAADPr) family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. This family includes eukaryotic macrodomain proteins such as human MacroD1 and MacroD2, and bacterial proteins such as Escherichia coli YmdB; these have been shown to be O-acetyl-ADP-ribose (OAADPr) deacetylases that efficiently catalyze the hydrolysis of OAADPr to produce ADP-ribose and free acetate. OAADPr is a sirtuin reaction product generated from the NAD+-dependent protein deacetylation reactions and has been implicated as a signaling molecule. By acting on mono-ADP-ribosylated substrates, OAADPr deacetylases may reverse cellular ADP-ribosylation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  819 KLFVLEEDLSRFPVDVVVNAANENLKHISGLAQALSKAAGPELQTECDQIvkeGGVVLPGNAVISKAGKLPCHHVIHAVG 898
Cdd:cd02908     1 KISLWRGDITKLEVDAIVNAANSSLLGGGGVDGAIHRAAGPELLEECRKL---GGVCPTGEAKITPGYNLPAKYVIHTVG 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 755553843  899 PRWKGDKVLECvSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLELcVANI-VSAIKEhFQHKRDthTLKKIYLV 976
Cdd:cd02908    78 PIGEGGVEEEP-ELLASCYRSSLELALENGLKSIAFPCISTGIYGYPNEE-AAEIaLNTVRE-WLEEHD--KIDRIIFV 151

Appr-1"-p processing enzyme; Function determined by Martzen et al. Extended family detected by reciprocal PSI-BLAST searches (unpublished results, and Pehrson _ Fuji).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843    826 DLSRFPVDVVVNAANENLKHISGLAQALSKAAGPEL-QTECDQivKEGGVVLPGNAVISKAGKLPCHHVIHAVGPRWkGD 904
Cdd:smart00506    8 DITKPRADAIVNAANSDGAHGGGVAGAIARAAGKALsKEEVRK--LAGGECPVGTAVVTEGGNLPAKYVIHAVGPRA-SG 84

                            90       100       110       120
                    ....*....|....*....|....*....|....*....|...
gi 755553843    905 KVLECVSLLKKVVRQSLSLAEEHRCRSIAMPAVSAGIFDFPLE 947
Cdd:smart00506   85 HSKEGFELLENAYRNCLELAIELGITSVALPLIGTGIYGVPKD 127

RNA recognition motif 2 in vertebrate poly [ADP-ribose] polymerase 14 (PARP-14); This subgroup corresponds to the RRM2 of PARP-14, also termed aggressive lymphoma protein 2, a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs. It is expressed in B lymphocytes and interacts with the IL-4-induced transcription factor Stat6. It plays a fundamental role in the regulation of IL-4-induced B-cell protection against apoptosis after irradiation or growth factor withdrawal. It mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. PARP-14 acts as a transcriptional switch for Stat6-dependent gene activation. In the presence of IL-4, PARP-14 activates transcription by facilitating the binding of Stat6 to the promoter and release of HDACs from the promoter with an IL-4 signal. In contrast, in the absence of a signal, PARP-14 acts as a transcriptional repressor by recruiting HDACs. Absence of PARP-14 protects against Myc-induced developmental block and lymphoma. Thus, PARP-14 may play an important role in Myc-induced oncogenesis. Additional research indicates that PARP-14 is also a binding partner with phosphoglucose isomerase (PGI)/ autocrine motility factor (AMF). It can inhibit PGI/AMF ubiquitination, thus contributing to its stabilization and secretion. PARP-14 contains two N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), three tandem macro domains, and C-terminal region with sequence homology to PARP catalytic domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 755553843  231 TNVVRVENLPPGVDEYQLQLFFENPFNGGGRVARVECFPEESSALVEFCDSKVLDTVMAKTHSYNKMPLSVFPYY 305
Cdd:cd12543     1 TCKIRAENLPPNTNSDYLMLYFENPYNGGIEVDGVTVDPEEESAIITFADPKDVQKIIALKHQFNKMPFSVLPYY 75

macrodomain, Af1521-like family; Macrodomains are found in a variety of proteins with diverse cellular functions, as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Macrodomains can recognize ADP-ribose (ADPr) in both its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (OAADPr), and even in ligands unrelated to ADPr. The macrodomains in this family show similarity to Af1521, a protein from Archaeoglobus fulgidus containing a stand-alone macrodomain. Af1521 binds ADP-ribose and exhibits phosphatase activity toward ADP-ribose-1"-monophosphate (Appr-1"-p). Also included in this family are the N-terminal (or first) macrodomains of BAL (B-aggressive lymphoma) proteins which contain multiple macrodomains, such as the first macrodomain of mono-ADP-ribosyltransferase PARP14 (PARP-14, also known as ADP-ribosyltransferase diphtheria toxin-like 8, ATRD8, B aggressive lymphoma protein 2, or BAL2). Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcriptional repressors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1243 ILFQVATGNIIKEVADVIVNSTTLTFDLKSGVSKAILEGAGQNVEQECSLLAKQsnHGYI------VTGGGLLQCKNIIH 1316
Cdd:cd02907     2 IKVSVYKGDITKEKVDAIVNAANERLKHGGGVAGAISKAGGPEIQEECDKYIKK--NGKLrvgevvVTSAGKLPCKYVIH 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 755553843 1317 VVG--GNDVKKSVSC---------VLEECEQRNYSSICLPAIGTGNAQQDPNVVAKAIIDAIEEFVQKKSVQAVKRV 1382
Cdd:cd02907    80 AVGprWSGGSKEECEdllykavlnSLEEAEELKATSIAIPAISSGIFGFPLDLCAEAIVEAIKDFSESNSSSSLKEI 156

Poly(ADP-ribose) polymerase catalytic domain; Poly(ADP-ribose) polymerase catalyzes the covalent attachment of ADP-ribose units from NAD+ to itself and to a limited number of other DNA binding proteins, which decreases their affinity for DNA. Poly(ADP-ribose) polymerase is a regulatory component induced by DNA damage. The carboxyl-terminal region is the most highly conserved region of the protein. Experiments have shown that a carboxyl 40 kDa fragment is still catalytically active.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  1649 EYNMVASAFRQT-----CSNFFIEKIERIQNPALWRRYQAYKKsmdekngnVRNEKHLFHGTEASSLPQLNSNGF--NRS 1721
Cdd:pfam00644    3 EYQIIEKYFLSThdpthGYPLFILEIFRVQRDGEWERFQPKKK--------LRNRRLLWHGSRLTNFLGILSQGLriAPP 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  1722 YAGKNATAYGKGTYFAVKASYSAcdTYSRPD-TNGRKYMYYVRVLTGN------------------YTNG--------NA 1774
Cdd:pfam00644   75 EAPVTGYMFGKGIYFADDASKSA--NYCPPSeAHGNGLMLLSEVALGDmnelkkadyaeklppgkhSVKGlgktapesFV 152

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*...
gi 755553843  1775 SLIVPPSRDPQnaADLYDTVtdnDKNPSIFVVFYDNQTYPEYLITFRQ 1822
Cdd:pfam00644  153 DLDGVPLGKLV--ATGYDSS---VLLYNEYVVYNVNQVRPKYLLEVKF 195

O-acetyl-ADP-ribose deacetylase (regulator of RNase III), contains Macro domain [Translation, ribosomal structure and biogenesis];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1046 AIVNSISPDLKLNKGpLSQAFLEKAGPKLQEE---LTRSGQgvsVDVGTILQTSGCNLNSRHVFHVVPPPWKSNNSAwSL 1122
Cdd:COG2110    15 AIVNAANSSLLGGGG-VAGAIHRAAGPELLEEcrrLCKQGG---CPTGEAVITPAGNLPAKYVIHTVGPVWRGGGPS-EE 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843 1123 KIMKNIIRDCLKTTENLSLQSIAFPAIGTGNLRFPKPEFAKLIISEVLKFSSRNqlKTLQEVQFLLHpkDHENIQAFSDE 1202
Cdd:COG2110    90 ELLASCYRNSLELAEELGIRSIAFPAIGTGVGGFPWEEAAPIAVETLRDFLEEH--PSLEEVRFVLF--DEEDYEAYRRA 165

                  ...
gi 755553843 1203 FDK 1205
Cdd:COG2110   166 LAR 168

X-domain (or Mac1 domain) of viral non-structural protein 3 and related macrodomains; The X-domain, also called Mac1, is the macrodomain found in riboviral non-structural protein 3 (Nsp3), including the Nsp3 of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) as well as SARS-CoV-2, and other coronaviruses (alpha-, beta-, gamma-, and deltacoronavirus), among others. The SARS-CoV-2 Nsp3 Mac1 is highly conserved among all CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. It appears to counter host-mediated antiviral ADP-ribosylation, a post-translational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Assays show that the de-MARylating activity leads to a rapid loss of substrate, and that Mac1 could not hydrolyze poly-ADP-ribose; thus, Mac1 is a MAR-hydrolase (mono-ADP ribosylhydrolase). Mac1 was originally named ADP-ribose-1"-phosphatase (ADRP) based on data demonstrating that it could remove the phosphate group from ADP-ribose-1"-phosphate; however, activity was modest and was unclear why this would impact a virus infection. This family also includes the X-domain of Avian infectious bronchitis virus (IBV) strain Beaudette coronavirus that does not bind ADP-ribose; the triple glycine sequence found in the X-domains of SARS-CoV and human coronavirus 229E (HCoV229E), which are involved in ADP-ribose binding, is not conserved in the IBV X-domain. SARS-CoVs have two other macrodomains referred to as the SUD-N (N-terminal subdomain, or Mac2) and SUD-M (middle SUD subdomain, or Mac3) of the SARS-unique domain (SUD), which also do not bind ADP-ribose; these bind G-quadruplexes (unusual nucleic-acid structures formed by consecutive guanosine nucleotides). SARS-CoV SUD-N and SUD-M are not included in this group.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755553843  833 DVVVNAANENLKHISGLAQALSKAAGPELQTECDQIvKEGGVVLPGNAVISKAGKLpCHHVIHAVGPRwKGDKvlECVSL 912
Cdd:cd21557     2 DVVVNAANENLKHGGGVAGAIYKATGGAFQKESDYI-KKNGPLKVGTAVLLPGHGL-AKNIIHVVGPR-KRKG--QDDQL 76