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{{STRUCTURE_1mjs| PDB=1mjs |  SCENE=  }}
==MH2 domain of transcriptional factor SMAD3==
===MH2 domain of transcriptional factor SMAD3===
<StructureSection load='1mjs' size='340' side='right' caption='[[1mjs]], [[Resolution|resolution]] 1.91&Aring;' scene=''>
{{ABSTRACT_PUBMED_12154125}}
== Structural highlights ==
<table><tr><td colspan='2'>[[1mjs]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MJS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MJS FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1mk2|1mk2]]</td></tr>
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMAD3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mjs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1mjs RCSB], [http://www.ebi.ac.uk/pdbsum/1mjs PDBsum]</span></td></tr>
<table>
== Disease ==
[[http://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:[http://omim.org/entry/613795 613795]]. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.<ref>PMID:21778426</ref> <ref>PMID:21217753</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9732876</ref> <ref>PMID:9892009</ref> <ref>PMID:10995748</ref> <ref>PMID:15241418</ref> <ref>PMID:15588252</ref> <ref>PMID:16156666</ref> <ref>PMID:16751101</ref> <ref>PMID:17327236</ref> <ref>PMID:16862174</ref> <ref>PMID:19289081</ref> <ref>PMID:19218245</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mj/1mjs_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.


==Disease==
Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.,Qin BY, Lam SS, Correia JJ, Lin K Genes Dev. 2002 Aug 1;16(15):1950-63. PMID:12154125<ref>PMID:12154125</ref>
[[http://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]].  Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:[http://omim.org/entry/613795 613795]]. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.<ref>PMID:21778426</ref><ref>PMID:21217753</ref>  


==Function==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[http://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9732876</ref><ref>PMID:9892009</ref><ref>PMID:10995748</ref><ref>PMID:15241418</ref><ref>PMID:15588252</ref><ref>PMID:16156666</ref><ref>PMID:16751101</ref><ref>PMID:17327236</ref><ref>PMID:16862174</ref><ref>PMID:19289081</ref><ref>PMID:19218245</ref>
</div>
 
== References ==
==About this Structure==
<references/>
[[1mjs]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MJS OCA].
__TOC__
 
</StructureSection>
==Reference==
<ref group="xtra">PMID:012154125</ref><references group="xtra"/><references/>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Correia, J J.]]
[[Category: Correia, J J.]]

Revision as of 20:27, 29 September 2014

MH2 domain of transcriptional factor SMAD3MH2 domain of transcriptional factor SMAD3

Structural highlights

1mjs is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:1mk2
Gene:SMAD3 (Homo sapiens)
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[SMAD3_HUMAN] Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:114500]. Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.[1] [2]

Function

[SMAD3_HUMAN] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.

Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.,Qin BY, Lam SS, Correia JJ, Lin K Genes Dev. 2002 Aug 1;16(15):1950-63. PMID:12154125[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA, Milewicz DM. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011 Sep 2;109(6):680-6. doi: 10.1161/CIRCRESAHA.111.248161. Epub 2011 , Jul 21. PMID:21778426 doi:10.1161/CIRCRESAHA.111.248161
  2. ↑ van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collee M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011 Feb;43(2):121-6. doi: 10.1038/ng.744. Epub 2011 Jan 9. PMID:21217753 doi:10.1038/ng.744
  3. ↑ Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature. 1998 Aug 27;394(6696):909-13. PMID:9732876 doi:10.1038/29814
  4. ↑ Lebrun JJ, Takabe K, Chen Y, Vale W. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999 Jan;13(1):15-23. PMID:9892009
  5. ↑ Qing J, Zhang Y, Derynck R. Structural and functional characterization of the transforming growth factor-beta -induced Smad3/c-Jun transcriptional cooperativity. J Biol Chem. 2000 Dec 8;275(49):38802-12. PMID:10995748 doi:10.1074/jbc.M004731200
  6. ↑ Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004 Jul 8;430(6996):226-31. PMID:15241418 doi:10.1038/nature02650
  7. ↑ Wang G, Long J, Matsuura I, He D, Liu F. The Smad3 linker region contains a transcriptional activation domain. Biochem J. 2005 Feb 15;386(Pt 1):29-34. PMID:15588252 doi:10.1042/BJ20041820
  8. ↑ Matsuura I, Wang G, He D, Liu F. Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. Biochemistry. 2005 Sep 20;44(37):12546-53. PMID:16156666 doi:10.1021/bi050560g
  9. ↑ Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, Shi Y, Chen YG, Meng A, Feng XH. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006 Jun 2;125(5):915-28. PMID:16751101 doi:10.1016/j.cell.2006.03.044
  10. ↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
  11. ↑ Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, Onozaki K, Hayashi H. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene. 2007 Jan 25;26(4):500-8. Epub 2006 Jul 24. PMID:16862174 doi:10.1038/sj.onc.1209826
  12. ↑ Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell. 2009 Mar;16(3):345-57. doi: 10.1016/j.devcel.2009.01.022. PMID:19289081 doi:10.1016/j.devcel.2009.01.022
  13. ↑ Wang G, Matsuura I, He D, Liu F. Transforming growth factor-{beta}-inducible phosphorylation of Smad3. J Biol Chem. 2009 Apr 10;284(15):9663-73. doi: 10.1074/jbc.M809281200. Epub 2009 , Feb 13. PMID:19218245 doi:10.1074/jbc.M809281200
  14. ↑ Qin BY, Lam SS, Correia JJ, Lin K. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. Genes Dev. 2002 Aug 1;16(15):1950-63. PMID:12154125 doi:10.1101/gad.1002002

1mjs, resolution 1.91Å

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