Mechanisms of voltage regulation of membrane transport
膜运输的电压调节机制
基本信息
- 批准号:10417430
- 负责人:
- 金额:$ 34.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsActivities of Daily LivingAddressAffectAngelman SyndromeArchitectureAttention deficit hyperactivity disorderBindingBiochemicalBiological AssayBiophysical ProcessC-terminalCCL21 geneCardiacCationsCell ProliferationCellsChargeChemicalsCholineComplementCouplesCryoelectron MicroscopyCuesCyclic AMPCyclic GMPCyclic NucleotidesCytoplasmic TailDNA Sequence AlterationDataDependenceDetergentsDevelopmentDiabetes MellitusDigestive System DisordersDiseaseDrug DesignElectrophysiology (science)EnzymesEpilepsyExhibitsFamilyFamily memberFluorescenceFoundationsHealthHeart failureHomeostasisHumanHydrogenHypertensionInterventionInvestigationIon Channel GatingIon ExchangeIon TransportIonsLengthLigandsLinkLiposomesMale InfertilityMalignant NeoplasmsMapsMeasuresMediatingMembraneMembrane ProteinsMembrane Transport ProteinsMethodsMicellesModelingMolecularMolecular ConformationMovementMusMuscular DystrophiesOrthologous GenePathologicPeptide HydrolasesPh+ ALLPharmacologyPhosphoric Monoester HydrolasesPhotobleachingPhysiological ProcessesPlayPoint MutationProtein FamilyProteinsProtonsRegulationReperfusion InjuryResolutionRoleSea UrchinsSodiumSodium ChlorideSperm CapacitationSperm MotilityStimulusStructureSystemTechniquesTestingThermodynamicsTransmembrane TransportVariantautism spectrum disorderbasedensitydesigndimerelectric fieldexperimental studyinnovationinsightinterfacialmembermutantnovelparticlepolypeptidereconstitutionreconstructionsingle moleculesodium ionsperm celltherapy designvoltage
项目摘要
Mechanisms of voltage regulation of membrane transport
SLC9 family of membrane transporters couple the import of sodium ions to export of protons.
They are vital for regulation of cytoplasmic and endosomal pH, which in turn affect several
physiological processes. Their disfunction has been linked to many diseases such as diabetes,
hypertension, heart failure and cancer. Genetic mutations in specific SLC9 members have also
been associated with Angelman-syndrome like disorders, ADHD, familial autism, epilepsies and
male infertility. The SLC9C1 is a unique member of the SLC9 family. Unlike other SLC9s which
feature a membrane delimited sodium-hydrogen exchange (NHE) domain and a usually short and
relatively unstructured C-terminal soluble domain, SLC9C1 combines an NHE, a voltage-sensing
domain (VSD) and a cyclic nucleotide binding domain (CNBD), interconnected via long, structured
linkers, in a single polypeptide. Recent foundational experiments have revealed that membrane
hyperpolarization and binding of cyclic nucleotides potentiates ion transport via SLC9C1. Its
unique design makes it impossible to predict how voltage and ligand regulation of this protein is
manifested at a structural level. SLC9C1 exhibits sperm-specific expression and has been shown
to be critical for sperm motility in mouse and humans. Sperm motility is robustly modulated by
changes in membrane voltage, intracellular cAMP levels and pH and all these stimuli influence
SLC9C1 mediated ion exchange directly, making it vital to understand the molecular
underpinnings of such diverse regulation. To this end, in this proposal we will integrate single-
particle cryo-electron microscopy and reconstruction techniques with biochemical and
electrophysiological methods to explore key biophysical mechanisms of SLC9C1. In Aim 1, we
will determine the first high-resolution structure of SLC9C1 and identify the key interactions
governing its organization. In Aim 2, we will elucidate the structural rearrangements in SLC9C1
triggered by cyclic nucleotide binding and use electrophysiology to test the role of a key interface
in mediating the regulatory effects of the CNBD. In Aim 3, we will determine how pH and permeant
ions affect the structure and function of SLC9C1. The proposal has a strong scientific foundation
built on our rigorous preliminary studies. It is innovative as it will provide the first snapshots of a
novel membrane protein in different conformations and test provocative hypotheses on the
mechanisms of voltage and cyclic nucleotide regulation of a transporter. The insights obtained
from our studies will aid structure-based drug design for treatment of male infertility. It will also
have broad implications on the structural and functional mechanisms of SLC9 regulation by their
cytoplasmic domains further underscoring its importance for human health.
膜传输的电压调节机制
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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Sandipan Chowdhury其他文献
Sandipan Chowdhury的其他文献
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{{ truncateString('Sandipan Chowdhury', 18)}}的其他基金
Mechanisms of voltage regulation of membrane transport
膜运输的电压调节机制
- 批准号:
10595025 - 财政年份:2022
- 资助金额:
$ 34.33万 - 项目类别:
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