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| | ==Solution structure of the F231L mutant ERCC1-XPF dimerization region== | | ==Solution structure of the F231L mutant ERCC1-XPF dimerization region== |
| - | <StructureSection load='2mut' size='340' side='right'caption='[[2mut]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2mut' size='340' side='right'caption='[[2mut]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2mut]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MUT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2mut]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MUT FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERCC1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ERCC4, ERCC11, XPF ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </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=2mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mut OCA], [https://pdbe.org/2mut PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mut RCSB], [https://www.ebi.ac.uk/pdbsum/2mut PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mut 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=2mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mut OCA], [https://pdbe.org/2mut PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mut RCSB], [https://www.ebi.ac.uk/pdbsum/2mut PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mut ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/ERCC1_HUMAN ERCC1_HUMAN]] Defects in ERCC1 are the cause of cerebro-oculo-facio-skeletal syndrome type 4 (COFS4) [MIM:[https://omim.org/entry/610758 610758]]. COFS is a degenerative autosomal recessive disorder of prenatal onset affecting the brain, eye and spinal cord. After birth, it leads to brain atrophy, hypoplasia of the corpus callosum, hypotonia, cataracts, microcornea, optic atrophy, progressive joint contractures and growth failure. Facial dysmorphism is a constant feature. Abnormalities of the skull, eyes, limbs, heart and kidney also occur.<ref>PMID:17273966</ref> [[https://www.uniprot.org/uniprot/XPF_HUMAN XPF_HUMAN]] Defects in ERCC4 are the cause of xeroderma pigmentosum complementation group F (XP-F) [MIM:[https://omim.org/entry/278760 278760]]; also known as xeroderma pigmentosum VI (XP6). XP-F is an autosomal recessive disease characterized by hypersensitivity of the skin to sunlight followed by high incidence of skin cancer and frequent neurologic abnormalities.<ref>PMID:8797827</ref> <ref>PMID:9580660</ref> <ref>PMID:9579555</ref> Defects in ERCC4 are a cause of XFE progeroid syndrome (XFEPS) [MIM:[https://omim.org/entry/610965 610965]]. This syndrome is illustrated by one patient who presented with dwarfism, cachexia and microcephaly.<ref>PMID:17183314</ref>
| + | [https://www.uniprot.org/uniprot/ERCC1_HUMAN ERCC1_HUMAN] Defects in ERCC1 are the cause of cerebro-oculo-facio-skeletal syndrome type 4 (COFS4) [MIM:[https://omim.org/entry/610758 610758]. COFS is a degenerative autosomal recessive disorder of prenatal onset affecting the brain, eye and spinal cord. After birth, it leads to brain atrophy, hypoplasia of the corpus callosum, hypotonia, cataracts, microcornea, optic atrophy, progressive joint contractures and growth failure. Facial dysmorphism is a constant feature. Abnormalities of the skull, eyes, limbs, heart and kidney also occur.<ref>PMID:17273966</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/ERCC1_HUMAN ERCC1_HUMAN]] Structure-specific DNA repair endonuclease responsible for the 5'-incision during DNA repair. [[https://www.uniprot.org/uniprot/XPF_HUMAN XPF_HUMAN]] Structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair. Involved in homologous recombination that assists in removing interstrand cross-link.<ref>PMID:19596235</ref>
| + | [https://www.uniprot.org/uniprot/ERCC1_HUMAN ERCC1_HUMAN] Structure-specific DNA repair endonuclease responsible for the 5'-incision during DNA repair. |
| | <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: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Boelens, R]] | + | [[Category: Boelens R]] |
| - | [[Category: Faridounnia, M]] | + | [[Category: Faridounnia M]] |
| - | [[Category: Folkers, G E]] | + | [[Category: Folkers GE]] |
| - | [[Category: Hoeijmakers, J H.J]] | + | [[Category: Hoeijmakers JHJ]] |
| - | [[Category: Jaspers, N G.J]] | + | [[Category: Jaspers NGJ]] |
| - | [[Category: Kaptein, R]] | + | [[Category: Kaptein R]] |
| - | [[Category: Kovacic, L]] | + | [[Category: Kovacic L]] |
| - | [[Category: Wienk, H]] | + | [[Category: Wienk H]] |
| - | [[Category: Ercc1-xpf]]
| + | |
| - | [[Category: F231l]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nucleotide excision repair]]
| + | |
| Structural highlights
Disease
ERCC1_HUMAN Defects in ERCC1 are the cause of cerebro-oculo-facio-skeletal syndrome type 4 (COFS4) [MIM:610758. COFS is a degenerative autosomal recessive disorder of prenatal onset affecting the brain, eye and spinal cord. After birth, it leads to brain atrophy, hypoplasia of the corpus callosum, hypotonia, cataracts, microcornea, optic atrophy, progressive joint contractures and growth failure. Facial dysmorphism is a constant feature. Abnormalities of the skull, eyes, limbs, heart and kidney also occur.[1]
Function
ERCC1_HUMAN Structure-specific DNA repair endonuclease responsible for the 5'-incision during DNA repair.
Publication Abstract from PubMed
The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe(231), Leu(231) lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation.
The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex.,Faridounnia M, Wienk H, Kovacic L, Folkers GE, Jaspers NG, Kaptein R, Hoeijmakers JH, Boelens R J Biol Chem. 2015 Aug 14;290(33):20541-55. doi: 10.1074/jbc.M114.635169. Epub, 2015 Jun 17. PMID:26085086[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR, Giglia-Mari G, Hoogstraten D, Kleijer WJ, Hoeijmakers JH, Vermeulen W. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am J Hum Genet. 2007 Mar;80(3):457-66. Epub 2007 Jan 29. PMID:17273966 doi:S0002-9297(07)60094-9
- ↑ Faridounnia M, Wienk H, Kovacic L, Folkers GE, Jaspers NG, Kaptein R, Hoeijmakers JH, Boelens R. The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex. J Biol Chem. 2015 Aug 14;290(33):20541-55. doi: 10.1074/jbc.M114.635169. Epub, 2015 Jun 17. PMID:26085086 doi:http://dx.doi.org/10.1074/jbc.M114.635169
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