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| | ==Structural Basis of Gene Regulation by the Grainyhead Transcription Factor Superfamily== | | ==Structural Basis of Gene Regulation by the Grainyhead Transcription Factor Superfamily== |
| - | <StructureSection load='5mpf' size='340' side='right' caption='[[5mpf]], [[Resolution|resolution]] 2.92Å' scene=''> | + | <StructureSection load='5mpf' size='340' side='right'caption='[[5mpf]], [[Resolution|resolution]] 2.92Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mpf]] 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=5MPF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MPF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mpf]] 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=5MPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MPF FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRHL1, LBP32, MGR, TFCP2L2 ([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]] 2.918Å</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=5mpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mpf OCA], [http://pdbe.org/5mpf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mpf RCSB], [http://www.ebi.ac.uk/pdbsum/5mpf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mpf 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=5mpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mpf OCA], [https://pdbe.org/5mpf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mpf RCSB], [https://www.ebi.ac.uk/pdbsum/5mpf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mpf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRHL1_HUMAN GRHL1_HUMAN]] Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' (PubMed:12175488, PubMed:18288204). Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity). Isoform 1 may function as an activator and isoform 2 as a repressor in tissues where both forms are expressed (PubMed:12175488).[UniProtKB:Q921D9]<ref>PMID:12175488</ref> <ref>PMID:18288204</ref> | + | [https://www.uniprot.org/uniprot/GRHL1_HUMAN GRHL1_HUMAN] Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' (PubMed:12175488, PubMed:18288204). Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity). Isoform 1 may function as an activator and isoform 2 as a repressor in tissues where both forms are expressed (PubMed:12175488).[UniProtKB:Q921D9]<ref>PMID:12175488</ref> <ref>PMID:18288204</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Heinemann, U]] | + | [[Category: Large Structures]] |
| - | [[Category: Ibraimi, I]] | + | [[Category: Heinemann U]] |
| - | [[Category: Ming, Q]] | + | [[Category: Ibraimi I]] |
| - | [[Category: Roske, Y]] | + | [[Category: Ming Q]] |
| - | [[Category: Schmidt-Ott, K M]] | + | [[Category: Roske Y]] |
| - | [[Category: Schuetz, A]] | + | [[Category: Schmidt-Ott KM]] |
| - | [[Category: Walentin, K]] | + | [[Category: Schuetz A]] |
| - | [[Category: Dna-binding domain]]
| + | [[Category: Walentin K]] |
| - | [[Category: Grainyhead]]
| + | |
| - | [[Category: Grhl1-dna complex]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| Structural highlights
Function
GRHL1_HUMAN Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' (PubMed:12175488, PubMed:18288204). Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity). Isoform 1 may function as an activator and isoform 2 as a repressor in tissues where both forms are expressed (PubMed:12175488).[UniProtKB:Q921D9][1] [2]
Publication Abstract from PubMed
Grainyhead (Grh)/CP2 transcription factors are highly conserved in multicellular organisms as key regulators of epithelial differentiation, organ development and skin barrier formation. In addition, they have been implicated as being tumor suppressors in a variety of human cancers. Despite their physiological importance, little is known about their structure and DNA binding mode. Here, we report the first structural study of mammalian Grh/CP2 factors. Crystal structures of the DNA-binding domains of grainyhead-like (Grhl) 1 and Grhl2 reveal a closely similar conformation with immunoglobulin-like core. Both share a common fold with the tumor suppressor p53, but differ in important structural features. The Grhl1 DNA-binding domain binds duplex DNA containing the consensus recognition element in a dimeric arrangement, supporting parsimonious target-sequence selection through two conserved arginine residues. We elucidate the molecular basis of a cancer-related mutation in Grhl1 involving one of these arginines, which completely abrogates DNA binding in biochemical assays and transcriptional activation of a reporter gene in a human cell line. Thus, our studies establish the structural basis of DNA target-site recognition by Grh transcription factors and reveal how tumor-associated mutations inactivate Grhl proteins. They may serve as points of departure for the structure-based development of Grh/CP2 inhibitors for therapeutic applications.
Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family.,Ming Q, Roske Y, Schuetz A, Walentin K, Ibraimi I, Schmidt-Ott KM, Heinemann U Nucleic Acids Res. 2018 Jan 4. pii: 4788346. doi: 10.1093/nar/gkx1299. PMID:29309642[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wilanowski T, Tuckfield A, Cerruti L, O'Connell S, Saint R, Parekh V, Tao J, Cunningham JM, Jane SM. A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead. Mech Dev. 2002 Jun;114(1-2):37-50. PMID:12175488
- ↑ Wilanowski T, Caddy J, Ting SB, Hislop NR, Cerruti L, Auden A, Zhao LL, Asquith S, Ellis S, Sinclair R, Cunningham JM, Jane SM. Perturbed desmosomal cadherin expression in grainy head-like 1-null mice. EMBO J. 2008 Mar 19;27(6):886-97. doi: 10.1038/emboj.2008.24. Epub 2008 Feb 21. PMID:18288204 doi:http://dx.doi.org/10.1038/emboj.2008.24
- ↑ Ming Q, Roske Y, Schuetz A, Walentin K, Ibraimi I, Schmidt-Ott KM, Heinemann U. Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family. Nucleic Acids Res. 2018 Jan 4. pii: 4788346. doi: 10.1093/nar/gkx1299. PMID:29309642 doi:http://dx.doi.org/10.1093/nar/gkx1299
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