4kmd

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{{STRUCTURE_4kmd| PDB=4kmd | SCENE= }}
 
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===Crystal structure of Sufud60-Gli1p===
 
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{{ABSTRACT_PUBMED_24217340}}
 
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==Disease==
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==Crystal structure of Sufud60-Gli1p==
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[[http://www.uniprot.org/uniprot/SUFU_HUMAN SUFU_HUMAN]] Defects in SUFU are a cause of medulloblastoma (MDB) [MIM:[http://omim.org/entry/155255 155255]]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Defects in SUFU play a role in predisposition to desmoplastic MDB. These tumors make up about 20 to 30% of medulloblastomas, have a more nodular architecture than 'classical' medulloblastoma, and may have a better prognosis.
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<StructureSection load='4kmd' size='340' side='right'caption='[[4kmd]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4kmd]] is a 2 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=4KMD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KMD FirstGlance]. <br>
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</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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4kmd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kmd OCA], [https://pdbe.org/4kmd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kmd RCSB], [https://www.ebi.ac.uk/pdbsum/4kmd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kmd ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/SUFU_HUMAN SUFU_HUMAN] Defects in SUFU are a cause of medulloblastoma (MDB) [MIM:[https://omim.org/entry/155255 155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Defects in SUFU play a role in predisposition to desmoplastic MDB. These tumors make up about 20 to 30% of medulloblastomas, have a more nodular architecture than 'classical' medulloblastoma, and may have a better prognosis.
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== Function ==
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[https://www.uniprot.org/uniprot/SUFU_HUMAN SUFU_HUMAN] Negative regulator in the hedgehog signaling pathway. Down-regulates GLI1-mediated transactivation of target genes. Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein. Negative regulator of beta-catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full length form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A).<ref>PMID:10564661</ref> <ref>PMID:10559945</ref> <ref>PMID:12068298</ref> <ref>PMID:10806483</ref> <ref>PMID:22365972</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Hedgehog (Hh) signalling regulates embryonic development and adult tissue homoeostasis. Mutations of its pathway components including Suppressor of Fused (Sufu) and Gli/Ci predispose to cancers and congenital anomalies. The Sufu-Gli protein complex occupies a central position in the vertebrate Hh signalling pathway, especially in mammals. Here structures of full-length human and Drosophila Sufu, the human Sufu-Gli complex, along with normal mode analysis and FRET measurement results, reveal that Sufu alternates between 'open' and 'closed' conformations. The 'closed' form of Sufu is stabilized by Gli binding and inhibited by Hh treatment, whereas the 'open' state of Sufu is promoted by Gli-dissociation and Hh signalling. Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription, tethering Gli in the cytoplasm and protecting Gli from the 26S proteasome-mediated degradation. Our study thus provides mechanistic insight into the mutual recognition and regulation between Sufu and Gli/Ci.
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==Function==
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Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci.,Zhang Y, Fu L, Qi X, Zhang Z, Xia Y, Jia J, Jiang J, Zhao Y, Wu G Nat Commun. 2013;4:2608. doi: 10.1038/ncomms3608. PMID:24217340<ref>PMID:24217340</ref>
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[[http://www.uniprot.org/uniprot/SUFU_HUMAN SUFU_HUMAN]] Negative regulator in the hedgehog signaling pathway. Down-regulates GLI1-mediated transactivation of target genes. Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein. Negative regulator of beta-catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full length form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A).<ref>PMID:10564661</ref> <ref>PMID:10559945</ref> <ref>PMID:12068298</ref> <ref>PMID:10806483</ref> <ref>PMID:22365972</ref> [[http://www.uniprot.org/uniprot/GLI1_HUMAN GLI1_HUMAN]] Acts as a transcriptional activator. May regulate the transcription of specific genes during normal development. May play a role in craniofacial development and digital development, as well as development of the central nervous system and gastrointestinal tract. Mediates SHH signaling and thus cell proliferation and differentiation.<ref>PMID:10806483</ref> <ref>PMID:11238441</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4kmd]] is a 2 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=4KMD OCA].
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</div>
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<div class="pdbe-citations 4kmd" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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<ref group="xtra">PMID:024217340</ref><references group="xtra"/><references/>
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<references/>
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[[Category: Human]]
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__TOC__
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[[Category: Qi, X.]]
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</StructureSection>
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[[Category: Wu, G.]]
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[[Category: Homo sapiens]]
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[[Category: Zhang, Y.]]
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[[Category: Large Structures]]
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[[Category: Zhang, Z.]]
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[[Category: Qi X]]
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[[Category: Protein binding-transcription complex]]
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[[Category: Wu G]]
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[[Category: Protein peptide complex]]
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[[Category: Zhang Y]]
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[[Category: Zhang Z]]

Current revision

Crystal structure of Sufud60-Gli1p

PDB ID 4kmd

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