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==Crystal structure of human SMAD2-MAN1 complex==
==Crystal structure of human SMAD2-MAN1 complex==
<StructureSection load='5zoj' size='340' side='right' caption='[[5zoj]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
<StructureSection load='5zoj' size='340' side='right'caption='[[5zoj]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5zoj]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZOJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZOJ FirstGlance]. <br>
<table><tr><td colspan='2'>[[5zoj]] is a 5 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=5ZOJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZOJ FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMAD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), MAN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.794&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zoj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zoj OCA], [http://pdbe.org/5zoj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zoj RCSB], [http://www.ebi.ac.uk/pdbsum/5zoj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zoj ProSAT]</span></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=5zoj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zoj OCA], [https://pdbe.org/5zoj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zoj RCSB], [https://www.ebi.ac.uk/pdbsum/5zoj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zoj ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/MAN1_HUMAN MAN1_HUMAN]] Isolated osteopoikilosis;Buschke-Ollendorff syndrome;12q14 microdeletion syndrome;Melorheostosis with osteopoikilosis. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/SMAD2_HUMAN SMAD2_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 SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9892009</ref> <ref>PMID:16751101</ref> <ref>PMID:17327236</ref> <ref>PMID:16862174</ref> <ref>PMID:19289081</ref>  [[http://www.uniprot.org/uniprot/MAN1_HUMAN MAN1_HUMAN]] Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.<ref>PMID:15601644</ref> <ref>PMID:15647271</ref> 
[https://www.uniprot.org/uniprot/SMAD2_HUMAN SMAD2_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 SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9892009</ref> <ref>PMID:16751101</ref> <ref>PMID:17327236</ref> <ref>PMID:16862174</ref> <ref>PMID:19289081</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Receptor-regulated SMAD (R-SMAD: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8) proteins are key transcription factors of the transforming growth factor-beta (TGF-beta) superfamily of cytokines. MAN1, an integral protein of the inner nuclear membrane, is a SMAD cofactor that terminates TGF-beta superfamily signals. Heterozygous loss-of-function mutations in MAN1 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. MAN1 interacts with MAD homology 2 (MH2) domains of R-SMAD proteins using its C-terminal U2AF homology motif (UHM) domain and UHM ligand motif (ULM) and facilitates R-SMAD dephosphorylation. Here, we report the structural basis for R-SMAD recognition by MAN1. The SMAD2-MAN1 and SMAD1-MAN1 complex structures show that an intramolecular UHM-ULM interaction of MAN1 forms a hydrophobic surface that interacts with a hydrophobic surface among the H2 helix, the strands beta8 and beta9, and the L3 loop of the MH2 domains of R-SMAD proteins. The complex structures also show the mechanism by which SMAD cofactors distinguish R-SMAD proteins that possess a highly conserved molecular surface.
 
Structural basis for receptor-regulated SMAD recognition by MAN1.,Miyazono KI, Ohno Y, Wada H, Ito T, Fukatsu Y, Kurisaki A, Asashima M, Tanokura M Nucleic Acids Res. 2018 Oct 13. pii: 5128924. doi: 10.1093/nar/gky925. PMID:30321401<ref>PMID:30321401</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5zoj" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Ito, T]]
[[Category: Large Structures]]
[[Category: Miyazono, K]]
[[Category: Ito T]]
[[Category: Ohno, Y]]
[[Category: Miyazono K]]
[[Category: Tanokura, M]]
[[Category: Ohno Y]]
[[Category: Complex]]
[[Category: Tanokura M]]
[[Category: Dna binding protein]]
[[Category: Tgf-beta signaling]]
[[Category: Transcription]]
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