4d2h
From Proteopedia
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| - | ''' | + | ==Crystal structure of the tetramerisation domain of human CtIP== |
| + | <StructureSection load='4d2h' size='340' side='right' caption='[[4d2h]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4d2h]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D2H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2H FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4d2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d2h RCSB], [http://www.ebi.ac.uk/pdbsum/4d2h PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/COM1_HUMAN COM1_HUMAN]] Seckel syndrome. Defects in RBBP8 are a cause of Seckel syndrome type 2 (SCKL2) [MIM:[http://omim.org/entry/606744 606744]]. SCKL2 is a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation.<ref>PMID:21998596</ref> Defects in RBBP8 are a cause of Jawad disease (JWDS) [MIM:[http://omim.org/entry/251255 251255]]. JWDS is a syndrome characterized by congenital microcephaly, moderately severe mental retardation, and symmetrical digital anomalies. Digital malformations of variable degree inclued hallux valgus, syndactyly of toes 4 and 5, short fifth fingers, single flexion crease of fifth fingers, polydactyly and synpolydactyly.<ref>PMID:21998596</ref> Note=Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk. Exhibits sensitivity to tamoxifen in certain breast cancer cell lines. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/COM1_HUMAN COM1_HUMAN]] Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in processing meiotic and mitotic double-strand breaks (DSBs) by ensuring both resection and intrachromosomal association of the broken ends. Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage. Promotes microhomology-mediated alternative end joining (A-NHEJ) during class-switch recombination and plays an essential role in chromosomal translocations.<ref>PMID:10764811</ref> <ref>PMID:10910365</ref> <ref>PMID:15485915</ref> <ref>PMID:16818604</ref> <ref>PMID:16581787</ref> <ref>PMID:17965729</ref> <ref>PMID:19202191</ref> <ref>PMID:19759395</ref> <ref>PMID:20064462</ref> <ref>PMID:20829486</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Mammalian CtIP protein has major roles in DNA double-strand break (DSB) repair. Although it is well established that CtIP promotes DNA-end resection in preparation for homology-dependent DSB repair, the molecular basis for this function has remained unknown. Here we show by biophysical and X-ray crystallographic analyses that the N-terminal domain of human CtIP exists as a stable homotetramer. Tetramerization results from interlocking interactions between the N-terminal extensions of CtIP's coiled-coil region, which lead to a 'dimer-of-dimers' architecture. Through interrogation of the CtIP structure, we identify a point mutation that abolishes tetramerization of the N-terminal domain while preserving dimerization in vitro. Notably, we establish that this mutation abrogates CtIP oligomer assembly in cells, thus leading to strong defects in DNA-end resection and gene conversion. These findings indicate that the CtIP tetramer architecture described here is essential for effective DSB repair by homologous recombination. | ||
| - | + | CtIP tetramer assembly is required for DNA-end resection and repair.,Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L Nat Struct Mol Biol. 2015 Jan 5. doi: 10.1038/nsmb.2937. PMID:25558984<ref>PMID:25558984</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Davies, O R]] | ||
| + | [[Category: Pellegrini, L]] | ||
[[Category: Sun, M]] | [[Category: Sun, M]] | ||
| - | [[Category: | + | [[Category: Ctip/rbbp8]] |
| - | [[Category: | + | [[Category: Dna-end resection]] |
| + | [[Category: Double-strand dna break repair]] | ||
| + | [[Category: Gene conversion]] | ||
| + | [[Category: Gene regulation]] | ||
| + | [[Category: Homologous recombination]] | ||
Revision as of 13:33, 14 January 2015
Crystal structure of the tetramerisation domain of human CtIP
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