Sterol Probes of Hedgehog Protein Processing
Hedgehog 蛋白加工的甾醇探针
基本信息
- 批准号:10292176
- 负责人:
- 金额:$ 44.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgonistAmino AcidsAnimalsAutomobile DrivingBindingBinding SitesBiochemicalBiological AssayC-terminalCatalytic DomainCell Differentiation processCell MaintenanceCell NucleusChemicalsChemistryCholesterolCleaved cellCongenital AbnormalityCrystallographyDataDiseaseEmbryonic DevelopmentEnvironmentErinaceidaeFluorescence Resonance Energy TransferFluorineFundingGoalsIndividualInstitutesJournalsKetonesLaboratoriesLibrariesLightLiteratureMalignant NeoplasmsMapsMedicalMembraneMethodsMethylationMutagenesisMutationN-terminalOrganic SynthesisPathway interactionsPositioning AttributePost-Translational Protein ProcessingProcessProtein PrecursorsProteinsPublishingReactionReporterRoleRouteSignal TransductionSignaling ProteinSiteStereoisomerSteroidsSterolsStructural BiologistStructureSubstrate InteractionSynthesis ChemistryTestingTimeUniversitiesVisitadult stem cellanalogbasecholesterol analogcholesterol biosynthesiscovalent bonddetection sensitivityfollow-upinhibitor/antagonistinteinmethyl groupsmoothened signaling pathwaystem cellsstructural biologyundergraduate student
项目摘要
PROJECT SUMMARY/ ABSTRACT
Hedgehog protein is unique by being covalently modified by cholesterol. This is critical to its
signaling role in embryonic development, and also in regulating adult stem cells. Malfunction of
hedgehog signaling leads to severe birth defects and is involved in many cancers.
Cholesterylation is essential to Hedgehog function and is catalyzed by the C-terminal domain of
the Hedgehog precursor protein. Many of the deleterious effects of mutations in cholesterol
biosynthesis are thought to involve Hedgehog signaling. The sterol binding region of the catalytic
domain is poorly understood because it is intrinsically too disordered to be amenable to
crystallography or protein NMR. The overall goal of this proposal to provide information about the
sterol-binding domain through the use of modified sterols. A library of 23 sterols bearing a methyl
group at each position of the sterol nucleus will be assembled by organic synthesis. The methyl
groups will be put in place by methylenation of the corresponding ketones, followed by reduction.
Both stereoisomers will be obtained at each secondary position. The angular methyl groups will
be introduced by literature methods. Where precedence does not exist (positions 8 and 9),
attempts will be made to apply methods for C5-methylation. This library will be tested by a
collaborator in a FRET-based Hedgehog processing assay. The results will establish which sites
of the sterol contact the binding site of the protein. The synthetic strategy allows adding steric bulk
(methyl to ethyl) to better define the binding region. Mutagenesis studies by the same collaborator
which regain function with a blocked sterol will determine which amino acids contact which regions
of the sterol molecule. Another library of 23 sterols, this time bearing fluorine atoms at each
position, will be synthesized using largely the same precursors that were used to make the methyl
sterol library. This library will be used for 19F-NMR based studies to map the binding site of the
protein. Covalent inhibitors of the processing reaction based on this library will also be synthesized
and studied. The NMR studies will be carried by a collaborating structural biologist. Hedgehog
protein modified by the sterol analogs may be useful to study downstream signaling interactions.
The two sterol libraries may be useful in the study of other protein-sterol interactions.
项目摘要/摘要
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nanomolar, Noncovalent Antagonism of Hedgehog Cholesterolysis: Exception to the "Irreversibility Rule" for Protein Autoprocessing Inhibition.
- DOI:10.1021/acs.biochem.1c00697
- 发表时间:2022-06-07
- 期刊:
- 影响因子:2.9
- 作者:Wagner, Andrew G.;Stagnitta, Robert T.;Xu, Zihan;Pezzullo, John L.;Kandel, Nabin;Giner, Jose-Luis;Covey, Douglas F.;Wang, Chunyu;Callahan, Brian P.
- 通讯作者:Callahan, Brian P.
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