Characterization of the p53-CBP/p300 Transcriptional Activator-Coactivator Complex
Characterization of the p53-CBP/p300 Transcriptional Activator-Coactivator Complex
批准号:
10077857
负责人:
Melody Sanders
金额:
$0.83万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-01 至 2021-02-01
关键词:
AcetyltransferaseAffinityApoptosisArchitectureAvidityBehaviorBindingBiochemicalBiological AssayBiological ProcessBiophysicsCREBBP geneCalorimetryCell ProliferationChromatinComplexCryoelectron MicroscopyDNA DamageDNA RepairDiseaseE1A-associated p300 proteinEP300 geneElectron MicroscopyEventGene ExpressionGenesGenetic TranscriptionGoalsHistonesInvestigationLengthLigandsLinkMeasuresMediatingMethodsModelingMolecularMolecular ConformationMutagenesisOncogenicPlayProteinsReactionRegulationResolutionRoentgen RaysRoleSignal PathwayStressStructural ModelsStructureTP53 geneThermodynamicsTitrationsTranscription CoactivatorTranscriptional ActivationTranscriptional Activation DomainTransferaseTumor Suppressor ProteinsVariantWorkbiophysical analysisbiophysical techniquesexperimental studyhistone acetyltransferaseholistic approachinsightparalogous geneparticleprotein protein interactionreconstitutionrecruitresponsetranscription factor
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
The CREB-binding protein (CBP) and its paralog p300 are master transcriptional coactivators that
integrate numerous signaling pathways and play critical roles in cell proliferation, differentiation,
apoptosis, and DNA repair. The biological functions of CBP and p300 are largely exerted through
multiple transcription factor interaction domains as well as a histone acetyl transferase (HAT)
domain. However, a structural model of how transcription factor complexes with CBP and p300
modulate coactivator function is lacking. A well-studied cellular partner of CBP and p300 is the
tumor suppressor protein p53. Several studies suggest that upon DNA damage CBP/p300 is
recruited by p53 to modify chromatin and aid in transcriptional activation of p53 target genes. It
has been hypothesized that each of the four transcriptional activation domains of an active p53
tetramer bind to four separate domains of a single CBP/p300 molecule, resulting in increased
avidity that further stabilizes the p53-CBP/p300 complex and enhances p53-mediated
transcription. However, the influence of p53 binding on local and global conformational changes
in CBP/p300 and its effect on histone acetyltransferase activity has yet to be defined. Using a
combination of single particle electron microscopy, solution biophysical and biochemical methods,
the goal of the proposed work is to develop a comprehensive structure-function model of
CBP/p300 in p53-mediated transcriptional activation.
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