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Conserved domains on  [gi|92859871|ref|NP_005576|]
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mothers against decapentaplegic homolog 6 [Homo sapiens]

Protein Classification

mothers against decapentaplegic homolog; mothers against decapentaplegic homolog 4 family protein( domain architecture ID 10180370)

mothers against decapentaplegic homolog such as SMAD1, SMAD5 and SMAD9 (also known as SMAD8); 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| mothers against decapentaplegic homolog 4 family protein such as 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)

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
MH2_SMAD_6 cd10499
C-terminal Mad Homology 2 (MH2) domain in SMAD6; The MH2 domain is located at the C-terminus ...
 322-494 1.29e-131

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.


:

Pssm-ID: 199824  Cd Length: 174  Bit Score: 378.40  E-value: 1.29e-131
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 322 SPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVW 401
Cdd:cd10499   1 SPDATKRSHWCSVAYWEHRTRVGRLYAVYDQSVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGYGILLSKEPDGVW 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 402 AYNRGEHPIFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSG-LQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQF 480
Cdd:cd10499  81 AYNRSEHPIFVNSPTLDIPGSRTLVVRKVPPGYSIKVFDYERSClLQHTAEPELADGPYDPNSVRISFAKGWGPCYSRQF 160

                       170
                ....*....|....
gi 92859871 481 ITSCPCWLEILLNN 494
Cdd:cd10499 161 ITSCPCWLEILLNN 174
MH1_SMAD_6 cd10493
N-terminal Mad Homology 1 (MH1) domain in SMAD6; The MH1 is a small DNA-binding domain present ...
 160-273 3.39e-64

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.


:

Pssm-ID: 199817  Cd Length: 113  Bit Score: 203.46  E-value: 3.39e-64
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 160 EARSRLLLLEQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAV 239
Cdd:cd10493   1 EGKSRQVALEQELKSVTYALLKRLKERSLDVLLEAVESRGGLPSGCVMVPRTELRLGGRRVPPQLLLCRLFRWPDLQHPA 80

                        90       100       110
                ....*....|....*....|....*....|....
gi 92859871 240 ELKPLCGCHSFaAAADGPTVCCNPYHFSRLCGPE 273
Cdd:cd10493  81 QLKALCHCQSF-GAQDGPTVCCNPYHYSRLCGPE 113
 
Name Accession Description Interval E-value
MH2_SMAD_6 cd10499
C-terminal Mad Homology 2 (MH2) domain in SMAD6; The MH2 domain is located at the C-terminus ...
 322-494 1.29e-131

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.


Pssm-ID: 199824  Cd Length: 174  Bit Score: 378.40  E-value: 1.29e-131
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 322 SPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVW 401
Cdd:cd10499   1 SPDATKRSHWCSVAYWEHRTRVGRLYAVYDQSVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGYGILLSKEPDGVW 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 402 AYNRGEHPIFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSG-LQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQF 480
Cdd:cd10499  81 AYNRSEHPIFVNSPTLDIPGSRTLVVRKVPPGYSIKVFDYERSClLQHTAEPELADGPYDPNSVRISFAKGWGPCYSRQF 160

                       170
                ....*....|....
gi 92859871 481 ITSCPCWLEILLNN 494
Cdd:cd10499 161 ITSCPCWLEILLNN 174
DWB smart00524
Domain B in dwarfin family proteins;
330-493 2.04e-82

Domain B in dwarfin family proteins;


Pssm-ID: 197770  Cd Length: 171  Bit Score: 252.62  E-value: 2.04e-82
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    330 HWCSVAYWEHRTRVGRLYAVYD--QAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGE 407
Cdd:smart00524   1 SWCKIAYYELNTRVGETFKVSSpsVTVDGFTDPSDGNRFCLGQLSNVNRNEATELIRKHIGKGVQLSYENGDVWLYNRSD 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    408 HPIFVNSPTLDAPGGRAL-VVRKVPPGYSIKVFDFERSGLQHAPEP-DAADGPYDPN---SVRISFAKGWGPCYSRQFIT 482
Cdd:smart00524  81 SPIFVQSPYLDEPGGRTLdTVHKLPPGYSIKVFDMEKFAQLLARELaKGFEGVYDLArmcTIRISFVKGWGPDYSRQTIT 160

                          170
                   ....*....|.
gi 92859871    483 SCPCWLEILLN 493
Cdd:smart00524 161 STPCWIEVHLN 171
MH2 pfam03166
MH2 domain; This is the MH2 (MAD homology 2) domain found at the carboxy terminus of MAD ...
 329-493 3.10e-82

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.


Pssm-ID: 460834  Cd Length: 172  Bit Score: 252.16  E-value: 3.10e-82
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   329 SHWCSVAYWEHRTRVGRLYAVYDQavSIFYDLP----QGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYN 404
Cdd:pfam03166   1 EIWCSVAYYELNTRVGEAFKVSSP--NVTVDGFtdpsDGNRFCLGLLSNVNRNEAVEKVRKHIGKGVRLSYDGGEVWIYN 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   405 RGEHPIFVNSPTLDAPGGRALV-VRKVPPGYSIKVFDFERS-GLQHAPEPDAADGPYDPN---SVRISFAKGWGPCYSRQ 479
Cdd:pfam03166  79 LSDHPVFVQSPYLNREAGRAPDtVHKVPPGESLKVFDMRKFqQLLSQELRRARLGPQDANklcSVRISFVKGWGPDYSRQ 158

                         170
                  ....*....|....
gi 92859871   480 FITSCPCWLEILLN 493
Cdd:pfam03166 159 DITSTPCWIEIHLH 172
MH1_SMAD_6 cd10493
N-terminal Mad Homology 1 (MH1) domain in SMAD6; The MH1 is a small DNA-binding domain present ...
 160-273 3.39e-64

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.


Pssm-ID: 199817  Cd Length: 113  Bit Score: 203.46  E-value: 3.39e-64
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 160 EARSRLLLLEQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAV 239
Cdd:cd10493   1 EGKSRQVALEQELKSVTYALLKRLKERSLDVLLEAVESRGGLPSGCVMVPRTELRLGGRRVPPQLLLCRLFRWPDLQHPA 80

                        90       100       110
                ....*....|....*....|....*....|....
gi 92859871 240 ELKPLCGCHSFaAAADGPTVCCNPYHFSRLCGPE 273
Cdd:cd10493  81 QLKALCHCQSF-GAQDGPTVCCNPYHYSRLCGPE 113
DWA smart00523
Domain A in dwarfin family proteins;
169-273 1.04e-43

Domain A in dwarfin family proteins;


Pssm-ID: 214708  Cd Length: 109  Bit Score: 149.84  E-value: 1.04e-43
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    169 EQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPR-ADLRLG--GQPAPPQLLLGRLFRWPDLQHAVELKPLC 245
Cdd:smart00523   3 EKWAKKATESLLKKLKKKQLEELLQAVESKGGPPTRCVLIPRsLDGRLQvaHRKGLPHVLYCRLFRWPDLQSPHELKALP 82

                           90       100
                   ....*....|....*....|....*...
gi 92859871    246 GCHSfAAAADGPTVCCNPYHFSRLCGPE 273
Cdd:smart00523  83 TCEH-AFESKSDEVCCNPYHYSRVERPE 109
MH1 pfam03165
MH1 domain; The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related ...
 172-270 1.42e-37

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.


Pssm-ID: 460833  Cd Length: 103  Bit Score: 133.27  E-value: 1.42e-37
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   172 LKTVTYSLLKRLKERS--LDTLLEAVESRGGVPGGCVLVPRA-DLRLG--GQPAPPQLLLGRLFRWPDLQHAVELKPLCG 246
Cdd:pfam03165   1 LKKAVESLLKKLKKKIqqLEELELAVESRGDPPTGCVTIPRSlDGRLQvaGRKGLPHVIYCRLWRWPDLQSQHELKAIPT 80

                          90       100
                  ....*....|....*....|....
gi 92859871   247 ChSFAAAADGPTVCCNPYHFSRLC 270
Cdd:pfam03165  81 C-ETAFESKKDEVCINPYHYSRVE 103
 
Name Accession Description Interval E-value
MH2_SMAD_6 cd10499
C-terminal Mad Homology 2 (MH2) domain in SMAD6; The MH2 domain is located at the C-terminus ...
 322-494 1.29e-131

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.


Pssm-ID: 199824  Cd Length: 174  Bit Score: 378.40  E-value: 1.29e-131
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 322 SPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVW 401
Cdd:cd10499   1 SPDATKRSHWCSVAYWEHRTRVGRLYAVYDQSVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGYGILLSKEPDGVW 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 402 AYNRGEHPIFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSG-LQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQF 480
Cdd:cd10499  81 AYNRSEHPIFVNSPTLDIPGSRTLVVRKVPPGYSIKVFDYERSClLQHTAEPELADGPYDPNSVRISFAKGWGPCYSRQF 160

                       170
                ....*....|....
gi 92859871 481 ITSCPCWLEILLNN 494
Cdd:cd10499 161 ITSCPCWLEILLNN 174
MH2_I-SMAD cd10496
C-terminal Mad Homology 2 (MH2) domain in Inhibitory SMADs; The MH2 domain is located at the ...
 331-493 2.36e-99

C-terminal Mad Homology 2 (MH2) domain in Inhibitory 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, which prevents it from forming a complex with SMAD4. SMAD6 and SMAD7 are inhibitory SMADs (I-SMADs) that function as negative regulators of signaling mediated by the TGF-beta superfamily. SMAD6 specifically inhibits bone morphogenetic protein (BMP) type I receptor mediated signaling, while SMAD7 enhances muscle differentiation and is often associated with cancer, tissue fibrosis and inflammatory diseases.


Pssm-ID: 199821  Cd Length: 165  Bit Score: 295.80  E-value: 2.36e-99
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 331 WCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQ-RSESVRRTRSKIGFGILLSKEPDGVWAYNRGEHP 409
Cdd:cd10496   1 WCTIAYWELRERVGRLYPVKQPAVNIFDDLPKGDGFCLGALNRQGnASEAVARVRSKIGLGVTLSREPDGVWIYNRSEYP 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 410 IFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSG-LQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQFITSCPCWL 488
Cdd:cd10496  81 IFVNSPTLDSPPSRNLLVTKVPPGYSLKVFDYERAAlLQRRDDHFSPQGPVDPNSVRISFVKGWGPNYSRQFITSCPCWL 160


                ....*
gi 92859871 489 EILLN 493
Cdd:cd10496 161 EILLN 165
MH2 cd00050
C-terminal Mad Homology 2 (MH2) domain; The MH2 domain is found in the SMAD (small mothers ...
 331-493 1.16e-91

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.


Pssm-ID: 199819  Cd Length: 170  Bit Score: 276.41  E-value: 1.16e-91
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 331 WCSVAYWEHRTRVGRLYAVY--DQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGEH 408
Cdd:cd00050   1 WCSIAYYELNTRVGELFHVYspSVAVDGFTDPSNGDRFCLGQLSNVNRNETIERTRRHIGKGVHLYYVGGEVWAECLSDH 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 409 PIFVNSPTLDAPGGR-ALVVRKVPPGYSIKVFDFERSGLQHAPEPD-----AADGPYDPnSVRISFAKGWGPCYSRQFIT 482
Cdd:cd00050  81 AIFVQSRNLDYPHGRhPLTVCKIPPGCSIKVFDNQEFAQLLHQSVNtgfegVYELTKMC-TIRMSFVKGWGPEYHRQDIT 159

                       170
                ....*....|.
gi 92859871 483 SCPCWLEILLN 493
Cdd:cd00050 160 STPCWIEIHLH 170
DWB smart00524
Domain B in dwarfin family proteins;
330-493 2.04e-82

Domain B in dwarfin family proteins;


Pssm-ID: 197770  Cd Length: 171  Bit Score: 252.62  E-value: 2.04e-82
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    330 HWCSVAYWEHRTRVGRLYAVYD--QAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGE 407
Cdd:smart00524   1 SWCKIAYYELNTRVGETFKVSSpsVTVDGFTDPSDGNRFCLGQLSNVNRNEATELIRKHIGKGVQLSYENGDVWLYNRSD 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    408 HPIFVNSPTLDAPGGRAL-VVRKVPPGYSIKVFDFERSGLQHAPEP-DAADGPYDPN---SVRISFAKGWGPCYSRQFIT 482
Cdd:smart00524  81 SPIFVQSPYLDEPGGRTLdTVHKLPPGYSIKVFDMEKFAQLLARELaKGFEGVYDLArmcTIRISFVKGWGPDYSRQTIT 160

                          170
                   ....*....|.
gi 92859871    483 SCPCWLEILLN 493
Cdd:smart00524 161 STPCWIEVHLN 171
MH2 pfam03166
MH2 domain; This is the MH2 (MAD homology 2) domain found at the carboxy terminus of MAD ...
 329-493 3.10e-82

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.


Pssm-ID: 460834  Cd Length: 172  Bit Score: 252.16  E-value: 3.10e-82
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   329 SHWCSVAYWEHRTRVGRLYAVYDQavSIFYDLP----QGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYN 404
Cdd:pfam03166   1 EIWCSVAYYELNTRVGEAFKVSSP--NVTVDGFtdpsDGNRFCLGLLSNVNRNEAVEKVRKHIGKGVRLSYDGGEVWIYN 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   405 RGEHPIFVNSPTLDAPGGRALV-VRKVPPGYSIKVFDFERS-GLQHAPEPDAADGPYDPN---SVRISFAKGWGPCYSRQ 479
Cdd:pfam03166  79 LSDHPVFVQSPYLNREAGRAPDtVHKVPPGESLKVFDMRKFqQLLSQELRRARLGPQDANklcSVRISFVKGWGPDYSRQ 158

                         170
                  ....*....|....
gi 92859871   480 FITSCPCWLEILLN 493
Cdd:pfam03166 159 DITSTPCWIEIHLH 172
MH2_SMAD_7 cd10500
C-terminal Mad Homology 2 (MH2) domain in SMAD7; The MH2 domain is located at the C-terminus ...
 329-493 1.63e-71

C-terminal Mad Homology 2 (MH2) domain in SMAD7; 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. SMAD7, an inhibitory or antagonistic SMAD (I-SMAD), acts as a negative regulator of signaling mediated by the TGF-beta superfamily of 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. SMAD7 and SMAD6 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. Altered expression of SMAD7 is often associated with cancer, tissue fibrosis and inflammatory diseases.


Pssm-ID: 199825  Cd Length: 171  Bit Score: 224.92  E-value: 1.63e-71
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 329 SHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGEH 408
Cdd:cd10500   6 SHWCVVAYWEEKTRVGRLYSVQEPSLDIFYDLPQGNGFCLGQLNSDNKSQLVQKVRSKIGYGIQLTREVDGVWVYNRSSY 85

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 409 PIFVNSPTLDAPGGRALVVRKVPPGYSIKVFDFERSG-LQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQFITSCPCW 487
Cdd:cd10500  86 PIFIKSATLDNPDSRTLLVHKVFPGFSIKAFDYEKAYsLQRPNDHEFMQQPWTGFTVQISFVKGWGQCYTRQFISSCPCW 165


                ....*.
gi 92859871 488 LEILLN 493
Cdd:cd10500 166 LEVIFN 171
MH1_SMAD_6 cd10493
N-terminal Mad Homology 1 (MH1) domain in SMAD6; The MH1 is a small DNA-binding domain present ...
 160-273 3.39e-64

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.


Pssm-ID: 199817  Cd Length: 113  Bit Score: 203.46  E-value: 3.39e-64
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 160 EARSRLLLLEQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAV 239
Cdd:cd10493   1 EGKSRQVALEQELKSVTYALLKRLKERSLDVLLEAVESRGGLPSGCVMVPRTELRLGGRRVPPQLLLCRLFRWPDLQHPA 80

                        90       100       110
                ....*....|....*....|....*....|....
gi 92859871 240 ELKPLCGCHSFaAAADGPTVCCNPYHFSRLCGPE 273
Cdd:cd10493  81 QLKALCHCQSF-GAQDGPTVCCNPYHYSRLCGPE 113
DWA smart00523
Domain A in dwarfin family proteins;
169-273 1.04e-43

Domain A in dwarfin family proteins;


Pssm-ID: 214708  Cd Length: 109  Bit Score: 149.84  E-value: 1.04e-43
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871    169 EQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPR-ADLRLG--GQPAPPQLLLGRLFRWPDLQHAVELKPLC 245
Cdd:smart00523   3 EKWAKKATESLLKKLKKKQLEELLQAVESKGGPPTRCVLIPRsLDGRLQvaHRKGLPHVLYCRLFRWPDLQSPHELKALP 82

                           90       100
                   ....*....|....*....|....*...
gi 92859871    246 GCHSfAAAADGPTVCCNPYHFSRLCGPE 273
Cdd:smart00523  83 TCEH-AFESKSDEVCCNPYHYSRVERPE 109
MH1_SMAD_6_7 cd10489
N-terminal Mad Homology 1 (MH1) domain in SMAD6 and SMAD7; The MH1 is a small DNA-binding ...
 157-273 3.64e-42

N-terminal Mad Homology 1 (MH1) domain in SMAD6 and SMAD7; 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 SMAD6 and SMAD7, both inhibitory SMADs (I-SMADs) and negative regulators of signaling mediated by TGF-beta superfamily. SMAD6 specifically inhibits bone morphogenetic protein (BMP) type I receptor mediated signaling while SMAD7 enhances muscle differentiation and is often associated with cancer, tissue fibrosis and inflammatory diseases.


Pssm-ID: 199813  Cd Length: 119  Bit Score: 145.99  E-value: 3.64e-42
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 157 RSREARSRLLLLEQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRlgGQPAPPQLLLGRLFRWPDLQ 236
Cdd:cd10489   8 AHRTRHSQNPLEERDLRAAFHALLKRLKEKQLELLLQAVESRGGDYLACVLLPRRDPR--SMPQDPHVLCCQLFRWPDLR 85

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 92859871 237 HAVELKPLCGCHSfaaAADGPTVCCNPYHFSRLCGPE 273
Cdd:cd10489  86 HSSELKRLPTCES---AKDPVYVCCNPYHWSRLCRPE 119
MH1 cd00049
N-terminal Mad Homology 1 (MH1) domain; The MH1 is a small DNA-binding domain present in SMAD ...
 160-271 2.24e-41

N-terminal Mad Homology 1 (MH1) domain; 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. Receptor-regulated SMAD proteins (R-SMADs, including SMAD1, SMAD2, SMAD3, SMAD5, and SMAD9) are activated by phosphorylation by transforming growth factor (TGF)-beta type I receptors. The active R-SMAD associates with a common mediator SMAD (Co-SMAD or SMAD4) and other cofactors, which together translocate to the nucleus to regulate gene expression. The inhibitory or antagonistic SMADs (I-SMADs, including SMAD6 and SMAD7) negatively regulate TGF-beta signaling by competing with R-SMADs for type I receptor or Co-SMADs. MH1 domains of R-SMAD and SMAD4 contain a nuclear localization signal as well as DNA-binding activity. The activated R-SMAD/SMAD4 complex then binds with very low affinity to a DNA sequence CAGAC called SMAD-binding element (SBE) via the MH1 domain.


Pssm-ID: 199811  Cd Length: 121  Bit Score: 144.27  E-value: 2.24e-41
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 160 EARSRLLL------LEQELKTVTYSLLKRLKER-SLDTLLEAVESRGGVPGGCVLVPRA-DLRLG--GQPAPPQLLLGRL 229
Cdd:cd00049   1 PIVKRLLGwkqggeEEKWAKKAVKSLVKKLKEKkQLDSLEKAITTQGGVPSKCVTIPRSlDGRLQvaHRKGLPHVIYCRL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 92859871 230 FRWPDLQHAVELKPLCGCHsFAAAADGPTVCCNPYHFSRLCG 271
Cdd:cd00049  81 WRWPDLHSHHELKALELCQ-FAFNMKKDEVCVNPYHYQRVES 121
MH1 pfam03165
MH1 domain; The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related ...
 172-270 1.42e-37

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.


Pssm-ID: 460833  Cd Length: 103  Bit Score: 133.27  E-value: 1.42e-37
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871   172 LKTVTYSLLKRLKERS--LDTLLEAVESRGGVPGGCVLVPRA-DLRLG--GQPAPPQLLLGRLFRWPDLQHAVELKPLCG 246
Cdd:pfam03165   1 LKKAVESLLKKLKKKIqqLEELELAVESRGDPPTGCVTIPRSlDGRLQvaGRKGLPHVIYCRLWRWPDLQSQHELKAIPT 80

                          90       100
                  ....*....|....*....|....
gi 92859871   247 ChSFAAAADGPTVCCNPYHFSRLC 270
Cdd:pfam03165  81 C-ETAFESKKDEVCINPYHYSRVE 103
MH2_R-SMAD cd10495
C-terminal Mad Homology 2 (MH2) domain in receptor regulated SMADs; The MH2 domain is located ...
 331-495 7.58e-31

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.


Pssm-ID: 199820  Cd Length: 182  Bit Score: 117.87  E-value: 7.58e-31
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 331 WCSVAYWEHRTRVGRLYAVYDQAVSI--FYDLPQGSG-FCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGE 407
Cdd:cd10495   1 WCSISYYELNSRVGEQFKASNPSIIVdgFTDPSNNSDrFCLGLLSNVNRNATIENTRRHIGRGVHLFYVGGEVYAECLSD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 408 HPIFVNSPTLDAPGGRALV-VRKVPPGYSIKVFDFER-SGLQHAPEPDAADGPYDPN---SVRISFAKGWGPCYSRQFIT 482
Cdd:cd10495  81 SAIFVQSRNCNLRHGFHPAtVCKIPPGCSLKIFNNQSfAQLLEQSVNRGFEAVYELTkmcTIRISFVKGWGAEYHRQDVT 160

                       170
                ....*....|...
gi 92859871 483 SCPCWLEILLNNP 495
Cdd:cd10495 161 STPCWIEIHLHGP 173
MH1_SMAD_7 cd10494
N-terminal Mad Homology 1 (MH1) domain in SMAD7; The MH1 is a small DNA-binding domain present ...
 169-275 3.44e-30

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.


Pssm-ID: 199818  Cd Length: 123  Bit Score: 113.82  E-value: 3.44e-30
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 169 EQELKTVTYSLLKRLKERSLDTLLEAVESRGGVPGGCVLVP-RADLRLGGQPAPPQLLLGRLFRWPDLQHAVELKPLCGC 247
Cdd:cd10494  17 EAELKALTHSVLKKLKERQLEGLLQAVESRGGARTPCLLLPaRLDARLGQQSYSLPLLLCKVFRWPDLRHSSEVKRLSCC 96

                        90       100
                ....*....|....*....|....*...
gi 92859871 248 HSFaAAADGPTVCCNPYHFSRLCGPESP 275
Cdd:cd10494  97 ESY-GKINPELVCCNPHHLSRLCELESP 123
MH2_SMAD_4 cd10498
C-terminal Mad Homology 2 (MH2) domain in SMAD4; The MH2 domain is located at the C-terminus ...
 328-495 9.54e-29

C-terminal Mad Homology 2 (MH2) domain in SMAD4; 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. SMAD4, which belongs to the Dwarfin family of proteins, is involved in many cell functions such as differentiation, apoptosis, gastrulation, embryonic development and the 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, cervical cancer and pancreatic carcinoma, as well as in juvenile polyposis syndrome.


Pssm-ID: 199823  Cd Length: 222  Bit Score: 113.33  E-value: 9.54e-29
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 328 PSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYD---LPQGSG-FCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDG-VWA 402
Cdd:cd10498   1 PEYWCSIAYFELDTQVGETFKVPSSCPTVTVDgyvDPSGGNrFCLGQLSNVHRTEASERARLHIGKGVQLDCKGEGdVWL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 403 YNRGEHPIFVNSPTLDAPGGRA--LVVRKVPPGYSIKVFDFERSGLQ---------------------HAPEPDAADGPY 459
Cdd:cd10498  81 RCLSDHSVFVQSYYLDREAGRApgDAVHKIYPSAYIKVFDLRQCHRQmqqqaataqaaaaaqaaavagNIPGPGSVGGIA 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|...
gi 92859871 460 DPNS-----------------VRISFAKGWGPCYSRQFITSCPCWLEILLNNP 495
Cdd:cd10498 161 PAISlsaaagigvddlrrlciLRMSFVKGWGPDYPRQSIKETPCWIEIHLHRA 213
MH2_SMAD_2_3 cd10985
C-terminal Mad Homology 2 (MH2) domain in SMAD2 and SMAD3; The MH2 domain is located at the ...
 326-495 5.20e-28

C-terminal Mad Homology 2 (MH2) domain in SMAD2 and SMAD3; 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. SMAD2 and SMAD3 are receptor regulated SMADs (R-SMADs). SMAD2 regulates multiple cellular processes, such as cell proliferation, apoptosis and differentiation, while SMAD3 modulates signals of activin and TGF-beta.


Pssm-ID: 199826  Cd Length: 191  Bit Score: 110.40  E-value: 5.20e-28
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 326 TKPSHWCSVAYWEHRTRVGRLYAVYDQAVSI--FYDLPQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAY 403
Cdd:cd10985   4 CEPAFWCSISYYEMNTRVGETFHASQPSLTVdgFTDPSNSERFCLGLLSNVNRNPQVELTRRHIGKGVRLYYIGGEVFAE 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 404 NRGEHPIFVNSPTLDAP-GGRALVVRKVPPGYSIKVFDF-ERSGLQHAPEPDAADGPYDPN---SVRISFAKGWGPCYSR 478
Cdd:cd10985  84 CLSDSAIFVQSPNCNQRyGWHPATVCKIPPGCNLKIFNNqEFAALLSQSVNQGFEAVYQLTrmcTIRMSFVKGWGAEYRR 163

                       170
                ....*....|....*..
gi 92859871 479 QFITSCPCWLEILLNNP 495
Cdd:cd10985 164 QTVTSTPCWIELHLNGP 180
MH2_SMAD_1_5_9 cd10497
C-terminal Mad Homology 2 (MH2) domain in SMAD1, SMAD5 and SMAD9; The MH2 domain is located at ...
 327-495 5.69e-25

C-terminal Mad Homology 2 (MH2) domain in SMAD1, SMAD5 and SMAD9; 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. SMAD1, SMAD5 and SMAD9 (also known as SMAD8), are 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 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.


Pssm-ID: 199822  Cd Length: 201  Bit Score: 102.26  E-value: 5.69e-25
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 327 KPSHWCSVAYWEHRTRVGRLYAVYDQAVSI--FYDlPQGSG--FCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWA 402
Cdd:cd10497   3 EPKYWCSIAYYELNNRVGEAFHASSTSIIVdgFTD-PSNNSdrFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYA 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 403 YNRGEHPIFVNSPTLDAPGG-RALVVRKVPPGYSIKVFDF-ERSGLQHAPEPDAADGPYDPN---SVRISFAKGWGPCYS 477
Cdd:cd10497  82 ECLSDSSIFVQSRNCNYHHGfHPTTVCKIPPGCSLKIFNNqEFAQLLSQSVNHGFEAVYELTkmcTIRMSFVKGWGAEYH 161

                       170
                ....*....|....*...
gi 92859871 478 RQFITSCPCWLEILLNNP 495
Cdd:cd10497 162 RQDVTSTPCWIEIHLHGP 179
MH1_SMAD_4 cd10492
N-terminal Mad Homology 1 (MH1) domain in SMAD4; The MH1 is a small DNA-binding domain present ...
 178-268 2.53e-17

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).


Pssm-ID: 199816  Cd Length: 125  Bit Score: 77.88  E-value: 2.53e-17
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 178 SLLKRLKER--SLDTLLEAVESRGGVPGGCVLVPRA-DLRL--GGQPAPPQLLLGRLFRWPDLqHAVELKPLCGC-HSFA 251
Cdd:cd10492  29 SLVKKLKDKrdELDSLITAITSNGAHPSKCVTIQRTlDGRLqvAGRKGFPHVIYARIWRWPDL-HKNELKHVKFCqYAFD 107

                        90
                ....*....|....*..
gi 92859871 252 AAADgpTVCCNPYHFSR 268
Cdd:cd10492 108 LKCD--SVCVNPYHYER 122
MH1_R-SMAD cd10488
N-terminal Mad Homology 1 (MH1) domain of receptor regulated SMADs; The MH1 is a small ...
 169-269 6.77e-14

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


Pssm-ID: 199812  Cd Length: 123  Bit Score: 68.37  E-value: 6.77e-14
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 169 EQELKtvtySLLKRLKERSLDTLLEAVESRGGVPGGCVLVPRA-DLRLG--GQPAPPQLLLGRLFRWPDLQHAVELKPLC 245
Cdd:cd10488  23 EKAVK----SLVKKLKKKGQLEELEKAISTQNVNTRCVTIPRSlDGRLQvsHRKGLPHVIYCRLWRWPDLQSHHELKPLE 98

                        90       100
                ....*....|....*....|....
gi 92859871 246 GCHsFAAAADGPTVCCNPYHFSRL 269
Cdd:cd10488  99 LCE-FAFNMKKEEVCINPYHYKRV 121
MH1_SMAD_1_5_9 cd10490
N-terminal Mad Homology 1 (MH1) domain in SMAD1, SMAD5 and SMAD9 (also known as SMAD8); The ...
 178-269 1.02e-12

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.


Pssm-ID: 199814  Cd Length: 124  Bit Score: 64.83  E-value: 1.02e-12
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 178 SLLKRLKER--SLDTLLEAVeSRGGVPGGCVLVPRA---DLRLGGQPAPPQLLLGRLFRWPDLQHAVELKPLCGChSFAA 252
Cdd:cd10490  28 SLVKKLKKKkgALEELEKAL-SCPGQPSKCVTIPRSldgRLQVSHRKGLPHVIYCRVWRWPDLQSHHELKPLECC-EFPF 105

                        90
                ....*....|....*..
gi 92859871 253 AADGPTVCCNPYHFSRL 269
Cdd:cd10490 106 GSKQKEVCINPYHYKRV 122
MH1_SMAD_2_3 cd10491
N-terminal Mad Homology 1 (MH1) domain in SMAD2 and SMAD3; The MH1 is a small DNA-binding ...
 178-269 1.89e-11

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.


Pssm-ID: 199815  Cd Length: 124  Bit Score: 61.39  E-value: 1.89e-11
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 92859871 178 SLLKRLKER-SLDTLLEAVESRGgVPGGCVLVPRA---DLRLGGQPAPPQLLLGRLFRWPDLQHAVELKPLCGCHsFAAA 253
Cdd:cd10491  29 SLVKKLKKTgGLDELEKAITTQN-SNTKCITIPRSldgRLQVSHRKGLPHVIYCRLWRWPDLQSHHELRAIETCE-YAFN 106

                        90
                ....*....|....*.
gi 92859871 254 ADGPTVCCNPYHFSRL 269
Cdd:cd10491 107 LKKDEVCVNPYHYQRV 122
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
  • Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
  • Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
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