Structural and Functional Studies of Adhesion GPCRs
粘附 GPCR 的结构和功能研究
基本信息
- 批准号:9376558
- 负责人:
- 金额:$ 3.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:ADGR1 geneAdhesionsAffectAgonistAttention deficit hyperactivity disorderBindingBinding ProteinsBiological AssayBrainCell AdhesionCell Adhesion MoleculesCell physiologyCellsChimera organismCleaved cellComplementComplexCouplingCrystallizationCuesCyclic AMPDataDevelopmentDiseaseElectron MicroscopyEngineeringExcitatory SynapseFLRT3 geneFamilyFibronectinsG-Protein-Coupled ReceptorsG-substrateGTP-Binding ProteinsGenerationsGenetic studyGoalsHumanImageImageryImmune systemImmunityIn VitroIntegral Membrane ProteinKnowledgeLaboratoriesLeadLeucine-Rich RepeatLigand BindingLigandsLinkMalignant NeoplasmsMechanicsMediatingMembraneMolecularMolecular ConformationMutagenesisMutateMutationN-terminalNervous system structureNeurobiologyNeurodevelopmental DisorderNeuronsOrganOrganismPeptidesPharmacologic SubstanceProcessProtein EngineeringProtocols documentationReceptor ActivationReceptor SignalingResearchResolutionRoleSchizophreniaSignal TransductionSignaling MoleculeStructural ProteinStructureSurfaceSystemTestingTransmembrane Domainalpha-latrotoxin receptoranticancer researchbasedeafnessexperimental studyextracellularhuman diseasein vivoinsightintercellular communicationinterdisciplinary approachmalignant neurologic neoplasmsmembermutantnervous system disordernovelnovel strategiesreceptorreceptor functionsuccesssynaptogenesissynthetic proteintool
项目摘要
Project Summary
The interplay between cellular adhesion and cellular signaling is essential for the development of all organs
such as the brain, and for the functioning of systems such as the immune and nervous systems. Adhesion G-
Protein Coupled Receptors (aGPCRs) are an understudied GPCR family that is thought to mediate intercellular
communication. They have emerging roles in multiple cellular functions and numerous human diseases
including neurological disorders and cancers. Unlike other GPCRs, aGPCRs have large extracellular regions
(ECR) that are autoproteolytically cleaved from their seven-pass transmembrane regions (TM) within a
conserved GPCR-Autoproteolysis INducing (GAIN) domain. The two fragments stay associated even after
cleavage. It is believed that ligand binding to the ECR causes shedding of the ECR, and exposure of a short
peptide that was previously hidden within the GAIN domain. This short peptide, called stachel, acts as a
tethered agonist and activates the transmembrane domain. However, the molecular mechanisms underlying
aGPCR activation remains poorly understood. The ultimate goal of the research proposed in this application is
to understand the stepwise mechanical details of aGPCR activation that start with adhesion of the ligand to the
ECR, continue with transduction of the adhesion signal from the ECR to the TM domain via the GAIN domain,
and end with the activation of the TM domain by the stachel peptide. We propose three Specific Aims that are
based on the major unknowns in these fundamentals steps for aGPCR activation: First, we aim to reveal if and
how extracellular adhesion starts signaling. Second, we aim to understand the role of the GAIN domain in
transducing the adhesion signal to the TM domain. Third, we aim to reveal the molecular details of aGPCR TM
domain activation by the stachel peptide. This research has a multi-disciplinary approach where the structural
and functional data performed in the PI's lab are complemented with electron microscopy, agonist/antagonist
generation via protein engineering, neuronal assays and G-protein expertise provided or performed by the
laboratories of close collaborators. The proposed experiments will build on exciting results obtained since we
started our lab, including the establishment of a robust in vitro signaling assay, the crystal structure of a ligand-
aGPCR complex, the engineering of a synthetic protein that inhibits an aGPCR function, and key advances in
the purification protocols of aGPCRs. We expect that this research will provide critical insights into the
mechanistic details of the aGPCR activation, helping to establish fundamental principles on intercellular
communication that are vital for numerous cellular functions.
项目总结
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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Demet Arac-Ozkan其他文献
Demet Arac-Ozkan的其他文献
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