N-terminal Mad Homology 1 (MH1) domain in SMAD1, SMAD5 and SMAD9 (also known as SMAD8); The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. MH1 binds to the DNA major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 domain is found in SMAD1, SMAD5 and SMAD9, all closely related receptor regulated SMADs (R-SMADs). SMAD1 plays an essential role in bone development and postnatal bone formation through activation by bone morphogenetic protein (BMP) type 1 receptor kinase. SMAD5 is involved in bone morphogenetic proteins (BMP) signal modulation and may also play a role in the pathway involving inhibition of hematopoietic progenitor cells by TGF-beta. SMAD9 mediates the differentiation of mesenchymal stem cells (MSCs) into tendon-like cells by inhibiting the osteogenic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944   9 FTSPAVKRLLGWKQGDEEEKWAEKAVDALVKKLKKKKGAMEELEKALSCPGQPSNCVTIPRSLDGRLQVSHRKGLPHVIY 88
Cdd:cd10490    1 FTSPAVKRLLGWKQGDEEEKWAEKAVDSLVKKLKKKKGALEELEKALSCPGQPSKCVTIPRSLDGRLQVSHRKGLPHVIY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767931944  89 CRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 132
Cdd:cd10490   81 CRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 124

Domain B in dwarfin family proteins;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944   270 HWCSIVYYELNNRVGEAFHASSTSVLVDGFTDPSNNkNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECLS 349
Cdd:smart00524   1 SWCKIAYYELNTRVGETFKVSSPSVTVDGFTDPSDG-NRFCLGQLSNVNRNEATELIRKHIGKGVQLSYENGDVWLYNRS 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944   350 DSSIFVQSRNCNYHHGFHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTKMCTIRMSFVKGWGAEYHRQDV 429
Cdd:smart00524  80 DSPIFVQSPYLDEPGGRTLDTVHKLPPGYSIKVFDMEKFAQLLARELAKGFEGVYDLARMCTIRISFVKGWGPDYSRQTI 159

                          170
                   ....*....|..
gi 767931944   430 TSTPCWIEIHLH 441
Cdd:smart00524 160 TSTPCWIEVHLN 171

N-terminal Mad Homology 1 (MH1) domain in SMAD1, SMAD5 and SMAD9 (also known as SMAD8); The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. MH1 binds to the DNA major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 domain is found in SMAD1, SMAD5 and SMAD9, all closely related receptor regulated SMADs (R-SMADs). SMAD1 plays an essential role in bone development and postnatal bone formation through activation by bone morphogenetic protein (BMP) type 1 receptor kinase. SMAD5 is involved in bone morphogenetic proteins (BMP) signal modulation and may also play a role in the pathway involving inhibition of hematopoietic progenitor cells by TGF-beta. SMAD9 mediates the differentiation of mesenchymal stem cells (MSCs) into tendon-like cells by inhibiting the osteogenic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944   9 FTSPAVKRLLGWKQGDEEEKWAEKAVDALVKKLKKKKGAMEELEKALSCPGQPSNCVTIPRSLDGRLQVSHRKGLPHVIY 88
Cdd:cd10490    1 FTSPAVKRLLGWKQGDEEEKWAEKAVDSLVKKLKKKKGALEELEKALSCPGQPSKCVTIPRSLDGRLQVSHRKGLPHVIY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767931944  89 CRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 132
Cdd:cd10490   81 CRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 124

MH1 domain; The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related proteins such as Smads. This domain is separated from the MH2 domain by a non-conserved linker region. The crystal structure of the MH1 domain shows that a highly conserved 11 residue beta hairpin is used to bind the DNA consensus sequence GNCN in the major groove, shown to be vital for the transcriptional activation of target genes. Not all examples of MH1 can bind to DNA however. Smad2 cannot bind DNA and has a large insertion within the hairpin that presumably abolishes DNA binding. A basic helix (H2) in MH1 with the nuclear localization signal KKLKK has been shown to be essential for Smad3 nuclear import. Smads also use the MH1 domain to interact with transcription factors such as Jun, TFE3, Sp1, and Runx.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944   30 AEKAVDALVKKLKKKKGAMEELEKALSCPG-QPSNCVTIPRSLDGRLQVSHRKGLPHVIYCRVWRWPDLQSHHELKPLEC 108
Cdd:pfam03165   1 LKKAVESLLKKLKKKIQQLEELELAVESRGdPPTGCVTIPRSLDGRLQVAGRKGLPHVIYCRLWRWPDLQSQHELKAIPT 80

                          90       100
                  ....*....|....*....|...
gi 767931944  109 CEFPFGSKQKEVCINPYHYKRVE 131
Cdd:pfam03165  81 CETAFESKKDEVCINPYHYSRVE 103

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767931944  161 QNEPHMPLNATFPDSFQQPNSHPFPHSPNS--------SYPNSPGSSSSTYPHSPTSSDPgSPFQMPADTPPPAYLPP 230
Cdd:pfam03154 322 QQRIHTPPSQSQLQSQQPPREQPLPPAPLSmphikpppTTPIPQLPNPQSHKHPPHLSGP-SPFQMNSNLPPPPALKP 398

Kinetoplastid RNA Editing Protein A2 (KREPA2); The KREPA2 (TbMP63) protein is a component of the parasitic protozoan's KREPA RNA editing catalytic complex (RECC). Kinetoplastid RNA editing (KRE) proteins occur as pairs or sets of related proteins in multiple complexes. KREPA complex is composed of six components (KREPA1-6), which share a conserved C-terminal region containing an oligonucleotide-binding (OB)-fold-like domain. KREPAs are responsible for the site-specific insertion and deletion of U nucleotides in the kinetoplastid mitochondria pre-messenger RNA. Apart from the conserved C-terminal OB-fold domain, KREPA1, KREPA2, and KREPA3 contain two conserved C2H2 zinc-finger domains. KREPA2 and kinetoplastid RNA editing ligase 1 (KREL1) are specific for ligation post-U-deletion and are paralogous to KREL2 and KREPA1 that are specific for ligation post-U-insertion. KREPA2, is critical for RECC stability and KREL1 integration into the complex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 178 QPNSHPFPHSPNSSypnsPGSSSSTYPHSP--TSSDPGSPFQMPADTPPPAYLPPEDPmtQDGSQPMDTnmMAPPLPSEI 255
Cdd:cd23959  160 PPPAKPLPAAAAAQ----QSSASPGEVASPfaSGTVSASPFATATDTAPSSGAPDGFP--AEASAPSPF--AAPASAASF 231

                         90
                 ....*....|....*....
gi 767931944 256 NRGDVQAVAYEEPKHWCSI 274
Cdd:cd23959  232 PAAPVANGEAATPTHACTI 250

C-terminal Mad Homology 2 (MH2) domain in receptor regulated SMADs; The MH2 domain is located at the C-terminus of the SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. The MH2 domain is responsible for type I receptor interaction, phosphorylation-triggered homo- and hetero-oligomerization, and transactivation. It is negatively regulated by the N-terminal MH1 domain. Receptor regulated SMADs (R-SMADs) include SMAD1, SMAD2, SMAD3, SMAD5 and SMAD9. SMAD1 plays an essential role in bone development and postnatal bone formation through activation by bone morphogenetic protein (BMP) type 1 receptor kinase. SMAD2 regulates multiple cellular processes, such as cell proliferation, apoptosis and differentiation, while SMAD3 modulates signals of activin and TGF-beta. SMAD5 is involved in BMP signal modulation, possibly playing a role in the pathway involving inhibition of hematopoietic progenitor cells by TGF-beta. SMAD9 (also known as SMAD8) can mediate the differentiation of mesenchymal stem cells into tendon-like cells by inhibiting the osteogenic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 271 WCSIVYYELNNRVGEAFHASSTSVLVDGFTDPSNNKNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECLSD 350
Cdd:cd10495    1 WCSISYYELNSRVGEQFKASNPSIIVDGFTDPSNNSDRFCLGLLSNVNRNATIENTRRHIGRGVHLFYVGGEVYAECLSD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 351 SSIFVQSRNCNYHHGFHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTKMCTIRMSFVKGWGAEYHRQDVT 430
Cdd:cd10495   81 SAIFVQSRNCNLRHGFHPATVCKIPPGCSLKIFNNQSFAQLLEQSVNRGFEAVYELTKMCTIRISFVKGWGAEYHRQDVT 160

                        170       180
                 ....*....|....*....|..
gi 767931944 431 STPCWIEIHLHGPLQWLDKVLT 452
Cdd:cd10495  161 STPCWIEIHLHGPLQWLDKVLT 182

C-terminal Mad Homology 2 (MH2) domain; The MH2 domain is found in the SMAD (small mothers against decapentaplegic) family of proteins and is responsible for type I receptor interactions, phosphorylation-triggered homo- and hetero-oligomerization, and transactivation. It is negatively regulated by the N-terminal MH1 domain which prevents it from forming a complex with SMAD4. The MH2 domain is multifunctional and provides SMADs with their specificity and selectivity, as well as transcriptional activity. Several transcriptional co-activators and repressors have also been reported to regulate SMAD signaling by interacting with the MH2 domain. Mutations in the MH2 domains of SMAD2 and especially SMAD4 have been detected in colorectal and other human cancers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 271 WCSIVYYELNNRVGEAFHASSTSVLVDGFTDPSNnKNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECLSD 350
Cdd:cd00050    1 WCSIAYYELNTRVGELFHVYSPSVAVDGFTDPSN-GDRFCLGQLSNVNRNETIERTRRHIGKGVHLYYVGGEVWAECLSD 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 351 SSIFVQSRNCNYHHGFHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTKMCTIRMSFVKGWGAEYHRQDVT 430
Cdd:cd00050   80 HAIFVQSRNLDYPHGRHPLTVCKIPPGCSIKVFDNQEFAQLLHQSVNTGFEGVYELTKMCTIRMSFVKGWGPEYHRQDIT 159

                        170
                 ....*....|.
gi 767931944 431 STPCWIEIHLH 441
Cdd:cd00050  160 STPCWIEIHLH 170

MH2 domain; This is the MH2 (MAD homology 2) domain found at the carboxy terminus of MAD related proteins such as Smads. This domain is separated from the MH1 domain by a non-conserved linker region. The MH2 domain mediates interaction with a wide variety of proteins and provides specificity and selectivity to Smad function and also is critical for mediating interactions in Smad oligomers. Unlike MH1, MH2 does not bind DNA. The well-studied MH2 domain of Smad4 is composed of five alpha helices and three loops enclosing a beta sandwich. Smads are involved in the propagation of TGF-beta signals by direct association with the TGF-beta receptor kinase which phosphorylates the last two Ser of a conserved 'SSXS' motif located at the C-terminus of MH2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  269 KHWCSIVYYELNNRVGEAFHASSTSVLVDGFTDPSNNkNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECL 348
Cdd:pfam03166   1 EIWCSVAYYELNTRVGEAFKVSSPNVTVDGFTDPSDG-NRFCLGLLSNVNRNEAVEKVRKHIGKGVRLSYDGGEVWIYNL 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  349 SDSSIFVQSRNCNYHHGFHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTKMCTIRMSFVKGWGAEYHRQD 428
Cdd:pfam03166  80 SDHPVFVQSPYLNREAGRAPDTVHKVPPGESLKVFDMRKFQQLLSQELRRARLGPQDANKLCSVRISFVKGWGPDYSRQD 159

                         170
                  ....*....|...
gi 767931944  429 VTSTPCWIEIHLH 441
Cdd:pfam03166 160 ITSTPCWIEIHLH 172

N-terminal Mad Homology 1 (MH1) domain of receptor regulated SMADs; The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. It binds to the major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 domain is found in all receptor regulated SMADs (R-SMADs) including SMAD1, SMAD2, SMAD3, SMAD5 and SMAD9. SMAD1 plays an essential role in bone development and postnatal bone formation through activation by bone morphogenetic protein (BMP) type 1 receptor kinase. SMAD2 regulates multiple cellular processes, such as cell proliferation, apoptosis and differentiation, while SMAD3 modulates signals of activin and TGF-beta. SMAD4, a common mediator SMAD (co-SMAD) binds R-SMADs, forming an oligomeric complex that binds to DNA and serves as a transcription factor. SMAD5 is involved in bone morphogenetic proteins (BMP) signal modulation, possibly playing a role in the pathway involving inhibition of hematopoietic progenitor cells by TGF-beta. SMAD9 (also known as SMAD8) can mediate the differentiation of mesenchymal stem cells (MSCs) into tendon-like cells by inhibiting the osteogenic pathway

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  12 PAVKRLLGWKQG---DEEEKWAEKAVDALVKKLKKKkGAMEELEKALSCPGQPSNCVTIPRSLDGRLQVSHRKGLPHVIY 88
Cdd:cd10488    1 PIVKRLLGWKKGeqnGEEEKWAEKAVKSLVKKLKKK-GQLEELEKAISTQNVNTRCVTIPRSLDGRLQVSHRKGLPHVIY 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767931944  89 CRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 132
Cdd:cd10488   80 CRLWRWPDLQSHHELKPLELCEFAFNMKKEEVCINPYHYKRVET 123

N-terminal Mad Homology 1 (MH1) domain in SMAD2 and SMAD3; The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. MH1 binds to the DNA major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 is found in SMAD2 as well as SMAD3. SMAD2 mediates the signal of the transforming growth factor (TGF)-beta, and thereby regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. It plays a role in the transmission of extracellular signals from ligands of the TGF-beta superfamily growth factors into the cell nucleus. SMAD3 modulates signals of activin and TGF-beta. It binds SMAD4, enabling its transmigration into the nucleus where it forms complexes with other proteins and acts as a transcription factor. Increased SMAD3 activity has been implicated in the pathogenesis of scleroderma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  10 TSPAVKRLLGWKQG--DEEEKWAEKAVDALVKKLKKKkGAMEELEKALSCPGQPSNCVTIPRSLDGRLQVSHRKGLPHVI 87
Cdd:cd10491    1 TPPVVKRLLGWKKGenGQEEKWSEKAVKSLVKKLKKT-GGLDELEKAITTQNSNTKCITIPRSLDGRLQVSHRKGLPHVI 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 767931944  88 YCRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRVES 132
Cdd:cd10491   80 YCRLWRWPDLQSHHELRAIETCEYAFNLKKDEVCVNPYHYQRVET 124

Domain A in dwarfin family proteins;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944    25 EEEKWAEKAVDALVKKLKKkkGAMEELEKALSCPG-QPSNCVTIPRSLDGRLQVSHRKGLPHVIYCRVWRWPDLQSHHEL 103
Cdd:smart00523   1 VEEKWAKKATESLLKKLKK--KQLEELLQAVESKGgPPTRCVLIPRSLDGRLQVAHRKGLPHVLYCRLFRWPDLQSPHEL 78

                           90       100       110
                   ....*....|....*....|....*....|.
gi 767931944   104 KPLECCEFPFGSKQKEVCINPYHYKRVESPV 134
Cdd:smart00523  79 KALPTCEHAFESKSDEVCCNPYHYSRVERPE 109

N-terminal Mad Homology 1 (MH1) domain in SMAD4; The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. MH1 binds to the DNA major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 belongs to SMAD4, a common mediator SMAD (co-SMAD), which belongs to the Dwarfin family of proteins and is involved in many cell functions such as differentiation, apoptosis, gastrulation, embryonic development and cell cycle. SMAD4 binds receptor regulated SMADs (R-SMADs) such as SMAD1 or SMAD2, and forms an oligomeric complex that binds to DNA and serves as a transcription factor. SMAD4 is often mutated in several cancers, such as multiploid colorectal cancer and pancreatic carcinoma, as well as in juvenile polyposis syndrome (JPS).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  14 VKRLLGWKQGDEEEKWAEKAVDALVKKLKKKKGAMEELEKALSCPG-QPSNCVTIPRSLDGRLQVSHRKGLPHVIYCRVW 92
Cdd:cd10492    7 VHSLMCHRQGGESESFAKRAIESLVKKLKDKRDELDSLITAITSNGaHPSKCVTIQRTLDGRLQVAGRKGFPHVIYARIW 86

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 767931944  93 RWPDLQShHELKPLECCEFPFGSKQKEVCINPYHYKRVES 132
Cdd:cd10492   87 RWPDLHK-NELKHVKFCQYAFDLKCDSVCVNPYHYERVVS 125

C-terminal Mad Homology 2 (MH2) domain in SMAD6; The MH2 domain is located at the C-terminus of the SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. The MH2 domain is responsible for type I receptor interaction, phosphorylation-triggered homo- and hetero-oligomerization, and transactivation. It is negatively regulated by the N-terminal MH1 domain, which prevents it from forming a complex with SMAD4. SMAD6, an inhibitory or antagonistic SMAD (I-SMAD), acts as a negative regulator of signaling mediated by the TGF-beta superfamily of ligands, by competing with SMAD4 and preventing the transcription of SMAD4's gene products. SMAD6 specifically inhibits bone morphogenetic protein (BMP) type I receptor mediated signaling. SMAD6 and SMAD7 act as critical mediators for effective TGF-beta I-mediated suppression of Interleukin-1/Toll-like receptor (IL-1R/TLR) signaling through simultaneous binding to Pellino-1, an adaptor protein of interleukin-1 receptor associated kinase 1 (IRAK1), via their MH2 domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 267 EPKHWCSIVYYELNNRVGEAFHASSTSVLVdgFTD-PSNNKnrFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYA 345
Cdd:cd10499    6 KRSHWCSVAYWEHRTRVGRLYAVYDQSVSI--FYDlPQGSG--FCLGQLNLEQRSESVRRTRSKIGYGILLSKEPDGVWA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 346 ECLSDSSIFVQSRNCNYHHGfHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTkmcTIRMSFVKGWGAEYH 425
Cdd:cd10499   82 YNRSEHPIFVNSPTLDIPGS-RTLVVRKVPPGYSIKVFDYERSCLLQHTAEPELADGPYDPN---SVRISFAKGWGPCYS 157

                        170
                 ....*....|....*
gi 767931944 426 RQDVTSTPCWIEIHL 440
Cdd:cd10499  158 RQFITSCPCWLEILL 172

N-terminal Mad Homology 1 (MH1) domain in SMAD6; The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins, which are signal transducers and transcriptional modulators that mediate multiple signaling pathways. MH1 binds to the DNA major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 belongs to SMAD6, an inhibitory SMAD (I-SMAD) or antagonistic SMAD, which acts as a negative regulator of signaling mediated by TGF-beta superfamily ligands, by competing with SMAD4 and preventing the transcription of SMAD4's gene products. SMAD6 specifically inhibits bone morphogenetic protein (BMP) type I receptor mediated signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  51 LEKALSCPGQPSNCVTIPRSldgRLQVSHRKGLPHVIYCRVWRWPDLQSHHELKPLECCEFPFGSKQKEVCINPYHYKRV 130
Cdd:cd10493   33 LEAVESRGGLPSGCVMVPRT---ELRLGGRRVPPQLLLCRLFRWPDLQHPAQLKALCHCQSFGAQDGPTVCCNPYHYSRL 109

                 ....
gi 767931944 131 ESPV 134
Cdd:cd10493  110 CGPE 113

N-terminal Mad Homology 1 (MH1) domain in SMAD7; The MH1 is a small DNA-binding domain present in SMAD (small mothers against decapentaplegic) family of proteins. It binds to the major groove in an unusual manner via a beta hairpin structure. It negatively regulates the functions of the MH2 domain, the C-terminal domain of SMAD. This MH1 belongs to SMAD7, an inhibitory SMAD (I-SMAD) or antagonistic SMAD, which acts as a negative regulator of signaling mediated by TGF-beta superfamily ligands, by blocking TGF-beta type 1 and activin association with the receptor as well as access to SMAD2. SMAD7 enhances muscle differentiation, playing pivotal roles in embryonic development and adult homoeostasis. Altered expression of SMAD7 is often associated with cancer, tissue fibrosis and inflammatory diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944  48 MEELEKALSCPGQP-SNCVTIPRSLDGRLQvSHRKGLPhVIYCRVWRWPDLQSHHELKPLECCEfPFGSKQKE-VCINPY 125
Cdd:cd10494   36 LEGLLQAVESRGGArTPCLLLPARLDARLG-QQSYSLP-LLLCKVFRWPDLRHSSEVKRLSCCE-SYGKINPElVCCNPH 112

                         90
                 ....*....|.
gi 767931944 126 HYKR---VESP 133
Cdd:cd10494  113 HLSRlceLESP 123

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767931944  161 QNEPHMPLNATFPDSFQQPNSHPFPHSPNS--------SYPNSPGSSSSTYPHSPTSSDPgSPFQMPADTPPPAYLPP 230
Cdd:pfam03154 322 QQRIHTPPSQSQLQSQQPPREQPLPPAPLSmphikpppTTPIPQLPNPQSHKHPPHLSGP-SPFQMNSNLPPPPALKP 398

Kinetoplastid RNA Editing Protein A2 (KREPA2); The KREPA2 (TbMP63) protein is a component of the parasitic protozoan's KREPA RNA editing catalytic complex (RECC). Kinetoplastid RNA editing (KRE) proteins occur as pairs or sets of related proteins in multiple complexes. KREPA complex is composed of six components (KREPA1-6), which share a conserved C-terminal region containing an oligonucleotide-binding (OB)-fold-like domain. KREPAs are responsible for the site-specific insertion and deletion of U nucleotides in the kinetoplastid mitochondria pre-messenger RNA. Apart from the conserved C-terminal OB-fold domain, KREPA1, KREPA2, and KREPA3 contain two conserved C2H2 zinc-finger domains. KREPA2 and kinetoplastid RNA editing ligase 1 (KREL1) are specific for ligation post-U-deletion and are paralogous to KREL2 and KREPA1 that are specific for ligation post-U-insertion. KREPA2, is critical for RECC stability and KREL1 integration into the complex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767931944 178 QPNSHPFPHSPNSSypnsPGSSSSTYPHSP--TSSDPGSPFQMPADTPPPAYLPPEDPmtQDGSQPMDTnmMAPPLPSEI 255
Cdd:cd23959  160 PPPAKPLPAAAAAQ----QSSASPGEVASPfaSGTVSASPFATATDTAPSSGAPDGFP--AEASAPSPF--AAPASAASF 231

                         90
                 ....*....|....*....
gi 767931944 256 NRGDVQAVAYEEPKHWCSI 274
Cdd:cd23959  232 PAAPVANGEAATPTHACTI 250