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| | ==Crystal structure of human SMAD1-MAN1 complex.== | | ==Crystal structure of human SMAD1-MAN1 complex.== |
| - | <StructureSection load='5zok' size='340' side='right' caption='[[5zok]], [[Resolution|resolution]] 2.85Å' scene=''> | + | <StructureSection load='5zok' size='340' side='right'caption='[[5zok]], [[Resolution|resolution]] 2.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zok]] is a 4 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=5ZOK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZOK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zok]] is a 4 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=5ZOK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZOK FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMAD1 ([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]] 2.85Å</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=5zok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zok OCA], [http://pdbe.org/5zok PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zok RCSB], [http://www.ebi.ac.uk/pdbsum/5zok PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zok 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=5zok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zok OCA], [https://pdbe.org/5zok PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zok RCSB], [https://www.ebi.ac.uk/pdbsum/5zok PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zok ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SMAD1_HUMAN SMAD1_HUMAN]] Defects in SMAD1 may be a cause of primary pulmonary hypertension (PPH1) [MIM:[http://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> [[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. | + | [https://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/SMAD1_HUMAN SMAD1_HUMAN]] Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.<ref>PMID:12097147</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/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> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | 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.
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| - | 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>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5zok" style="background-color:#fffaf0;"></div>
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| | == 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: Tanokura, M]] | + | [[Category: Miyazono K]] |
| - | [[Category: Complex]] | + | [[Category: Tanokura M]] |
| - | [[Category: Dna binding protein]]
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| - | [[Category: Tgf-beta signaling]]
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| - | [[Category: Transcription]]
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