View source for 9hwe


==SMAD4 MH2, residues 314-552==
<StructureSection load='9hwe' size='340' side='right'caption='[[9hwe]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9hwe]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HWE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HWE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9hwe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hwe OCA], [https://pdbe.org/9hwe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hwe RCSB], [https://www.ebi.ac.uk/pdbsum/9hwe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hwe ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SMAD4_HUMAN SMAD4_HUMAN] Defects in SMAD4 are a cause of pancreatic cancer (PNCA) [MIM:[https://omim.org/entry/260350 260350].  Defects in SMAD4 are a cause of juvenile polyposis syndrome (JPS) [MIM:[https://omim.org/entry/174900 174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.<ref>PMID:9811934</ref> <ref>PMID:12417513</ref>   Defects in SMAD4 are a cause of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:[https://omim.org/entry/175050 175050]. JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:[https://omim.org/entry/187300 187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.  Defects in SMAD4 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Defects in SMAD4 may be a cause of primary pulmonary hypertension (PPH1) [MIM:[https://omim.org/entry/178600 178600]. A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.<ref>PMID:21898662</ref>   Defects in SMAD4 are the cause of Myhre syndrome (MYHRS) [MIM:[https://omim.org/entry/139210 139210]. MYHRS is a syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.<ref>PMID:22243968</ref> <ref>PMID:22158539</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SMAD4_HUMAN SMAD4_HUMAN] Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9389648</ref> <ref>PMID:17327236</ref> 
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Condeminas M]]
[[Category: Macias MJ]]
[[Category: Pluta R]]
[[Category: Pous J]]
[[Category: Torner C]]