期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 10, 页码 3778-3783出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1113731109
关键词
crystal; DNA damage; p300; stress; tumor suppressor
资金
- Medical Research Council
- Cancer Research UK (CRUK)
- Leukemia Research Fund (LRF)
- Association for International Cancer Research (AICR)
- European Union (EU)
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- Genome Canada through Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- MRC [G9400953, G0500905, G1000807] Funding Source: UKRI
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [G1000807, G9400953, G0500905] Funding Source: researchfish
Activation of p53 target genes for tumor suppression depends on the stress-specific regulation of transcriptional coactivator complexes. Strap (stress-responsive activator of p300) is activated upon DNA damage by ataxia telangiectasia mutated (ATM) and Chk2 kinases and is a key regulator of the p53 response. In addition to antagonizing Mdm2, Strap facilitates the recruitment of p53 coactivators, including JMY and p300. Strap is a predicted TPR-repeat protein, but shows only limited sequence identity with any protein of known structure. To address this and to elucidate the molecular mechanism of Strap activity we determined the crystal structure of the full-length protein at 2.05 angstrom resolution. The structure of Strap reveals an atypical six tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain. This previously unseen domain organization provides an extended superhelical scaffold allowing for protein-protein as well as protein-DNA interaction. We show that both of the TPR and OB-fold domains localize to the chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.
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