Molecular mechanism of PIN1-mediated regulation of the nuclear receptor PPARy
PIN1介导的核受体PPARγ调节的分子机制
基本信息
- 批准号:10607310
- 负责人:
- 金额:$ 3.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdipocytesAffectAffinityAgonistAutomobile DrivingBindingBinding ProteinsBinding SitesBiological AssayBiologyC-terminalCell physiologyCellsClinicalComplementComplexCryoelectron MicroscopyDNA Binding DomainDataData CorrelationsDiabetes MellitusDiseaseEnzymesEpitopesFDA approvedGene Expression ProfilingGenesGenetic TranscriptionGleanHumanIn VitroInsulinInterferometryIsomeraseIsomerismIsotope LabelingKineticsLabelLengthLigand BindingLigand Binding DomainLigandsLipolysisMAPK1 geneMass Spectrum AnalysisMeasuresMediatingMediatorMetabolic syndromeMethodsModelingMolecularMolecular ConformationMonitorMutagenesisN-terminalNIMANMR SpectroscopyNon-Insulin-Dependent Diabetes MellitusNuclear Magnetic ResonanceNuclear ProteinNuclear ReceptorsPPAR gammaPatternPeptidesPeptidylprolyl IsomerasePharmaceutical PreparationsPhosphorylationPhosphotransferasesPlasmidsPopulationPost-Translational Protein ProcessingProlineProtein ConformationProtein RegionProteinsProteomicsRationalizationRegulationReporterRoleSiteStructureTertiary Protein StructureTherapeuticVertebral columnVisualizationX-Ray Crystallographyadipocyte differentiationantagonistbiophysical techniquescrosslinkexperimental studyflexibilitygenetic corepressorinsightinsulin sensitivityknock-downlipid biosynthesisoverexpressionprogramsrecruitsmall hairpin RNAstructural biologytooltranscription factor
项目摘要
Project Summary/Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand sensitive nuclear receptor and
master regulator of adipogenesis. There exist FDA approved drugs that bind the ligand binding domain (LBD) of
PPARγ to induce a well characterized conformational change, which alters the activity of this transcription factor.
However, the functionally critical N-terminal intrinsically disordered AF1 domain remains poorly understood from
a structural standpoint due to the limited number of biophysical methods that can provide atomic level detail of
binding interactions and AF1 conformational states. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1
(PIN1) is a known protein binding partner of PPARγ that exerts its catalytic activity specifically at pSer/pThr-Pro
motifs, facilitating the cis/trans isomerization of proline bonds along the peptide backbone. Preliminary data from
our lab and others suggest PIN1 binds the AF1 region of PPARγ with a much greater affinity than the LBD, an
observation which presents the opportunity to better understand the role of AF1 function in PPARγ biology. This
binding interaction suggests a cascade of post translational modifications (PTMs), including kinase-mediated
phosphorylation and PIN1 enzyme-catalyzed proline cist/trans isomerization of the AF1 region, may be
responsible for tuning the transcriptional activity of PPARγ and maintaining activation of adipogenic gene
programs. In this project I will use nuclear magnetic resonance (NMR) spectroscopy to monitor PTM
(phosphorylation and isomerization) induced changes in AF1 conformational states and correlate this data with
cellular function associated with PPARγ-mediated gene programs that influence adipogenesis and insulin
sensitization. Aim 1 of this project outlines the use of NMR methods to monitor and describe the phosphorylation-
dependent and isomerization-dependent conformational changes the AF1 domain undergoes. These NMR
studies will be complemented by kinetic and structural insight gleaned from biolayer interferometry (BLI)
experiments to measure binding affinity of AF1 peptides to PIN1, X-ray crystallography studies of PIN1 in
complex with AF1 peptides, and cross-linking mass spectrometry (XL-MS) using full length PPARγ and PIN1 to
identify intermolecular protein contacts which may not be exclusive to the AF1 domain. To correlate the structural
and molecular mechanisms described by Aim 1 with functional effects observed in cells, Aim 2 of this project
uses structure-guided mutagenesis, transcriptional reporter assays, and knockdown experiments in pre-
adipocytes to understand the role of PIN1 as a mediator of PPARγ function during adipogenesis. Gene
expression analysis and assays that measure cellular endpoints associated with PPARγ function will further
assess the roles of these PTMs within the AF1 domain in promoting adipogenic function.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher Conrad Williams其他文献
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