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| | ==Crystal Structure of the synthetic peptide iM10 in complex with the coiled-coil region of MITF== | | ==Crystal Structure of the synthetic peptide iM10 in complex with the coiled-coil region of MITF== |
| - | <StructureSection load='4c7n' size='340' side='right' caption='[[4c7n]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4c7n' size='340' side='right'caption='[[4c7n]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4c7n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C7N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C7N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4c7n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C7N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</scene></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]] 2.1Å</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=4c7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7n OCA], [http://pdbe.org/4c7n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c7n RCSB], [http://www.ebi.ac.uk/pdbsum/4c7n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7n ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</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=4c7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7n OCA], [https://pdbe.org/4c7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c7n RCSB], [https://www.ebi.ac.uk/pdbsum/4c7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7n ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/MITF_HUMAN MITF_HUMAN]] MITF-related melanoma and renal cell carcinoma predisposition syndrome;Clear cell renal carcinoma;Papillary renal cell carcinoma;Tietz syndrome;Waardenburg syndrome type 2;Ocular albinism with congenital sensorineural deafness. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/MITF_HUMAN MITF_HUMAN] MITF-related melanoma and renal cell carcinoma predisposition syndrome;Clear cell renal carcinoma;Papillary renal cell carcinoma;Tietz syndrome;Waardenburg syndrome type 2;Ocular albinism with congenital sensorineural deafness. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MITF_HUMAN MITF_HUMAN]] Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.<ref>PMID:10587587</ref> <ref>PMID:22647378</ref> | + | [https://www.uniprot.org/uniprot/MITF_HUMAN MITF_HUMAN] Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.<ref>PMID:10587587</ref> <ref>PMID:22647378</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: Einsle, O]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Gerhardt, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Kuekenshoener, T]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Wohlwend, D]] | + | [[Category: Einsle O]] |
| - | [[Category: Coiled-coil]] | + | [[Category: Gerhardt S]] |
| - | [[Category: Protein engineering]] | + | [[Category: Kuekenshoener T]] |
| - | [[Category: Transcription]] | + | [[Category: Wohlwend D]] |
| Structural highlights
Disease
MITF_HUMAN MITF-related melanoma and renal cell carcinoma predisposition syndrome;Clear cell renal carcinoma;Papillary renal cell carcinoma;Tietz syndrome;Waardenburg syndrome type 2;Ocular albinism with congenital sensorineural deafness. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry.
Function
MITF_HUMAN Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.[1] [2]
Publication Abstract from PubMed
The design and selection of peptides targeting cellular proteins is challenging and often yields candidates with undesired properties. Therefore we deployed a new selection system based on the twin-arginine translocase (TAT) pathway of Escherichia coli, named hitchhiker translocation (HiT) selection. A pool of alpha-helix encoding sequences was designed and selected for interference with the coiled coil domain (CC) of a melanoma-associated basic-helix-loop-helix-leucine-zipper (bHLHLZ) protein, the microphthalmia associated transcription factor (MITF). One predominant sequence (iM10) was enriched during selection and showed remarkable protease resistance, high solubility and thermal stability while maintaining its specificity. Furthermore, it exhibited nanomolar range affinity towards the target peptide. A mutation screen indicated that target-binding helices of increased homodimer stability and improved expression rates were preferred in the selection process. The crystal structure of the iM10/MITF-CC heterodimer (2.1A) provided important structural insights and validated our design predictions. Importantly, iM10 did not only bind to the MITF coiled coil, but also to the markedly more stable HLHLZ domain of MITF. Characterizing the selected variants of the semi-rational library demonstrated the potential of the innovative bacterial selection approach.
Improving coiled coil stability while maintaining specificity by a bacterial hitchhiker selection system.,Kukenshoner T, Wohlwend D, Niemoller C, Dondapati P, Speck J, Adeniran AV, Nieth A, Gerhardt S, Einsle O, Muller KM, Arndt KM J Struct Biol. 2014 Mar 12. pii: S1047-8477(14)00053-7. doi:, 10.1016/j.jsb.2014.03.002. PMID:24631970[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Takeda K, Takemoto C, Kobayashi I, Watanabe A, Nobukuni Y, Fisher DE, Tachibana M. Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Hum Mol Genet. 2000 Jan 1;9(1):125-32. PMID:10587587
- ↑ Genovese G, Ghosh P, Li H, Rettino A, Sioletic S, Cittadini A, Sgambato A. The tumor suppressor HINT1 regulates MITF and beta-catenin transcriptional activity in melanoma cells. Cell Cycle. 2012 Jun 1;11(11):2206-15. doi: 10.4161/cc.20765. Epub 2012 Jun 1. PMID:22647378 doi:http://dx.doi.org/10.4161/cc.20765
- ↑ Kukenshoner T, Wohlwend D, Niemoller C, Dondapati P, Speck J, Adeniran AV, Nieth A, Gerhardt S, Einsle O, Muller KM, Arndt KM. Improving coiled coil stability while maintaining specificity by a bacterial hitchhiker selection system. J Struct Biol. 2014 Mar 12. pii: S1047-8477(14)00053-7. doi:, 10.1016/j.jsb.2014.03.002. PMID:24631970 doi:http://dx.doi.org/10.1016/j.jsb.2014.03.002
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