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.
膜转运的电压调节机制
膜转运蛋白的SLC 9家族将钠离子的输入与质子的输出偶联。
它们对于调节细胞质和内体pH至关重要,这反过来又影响几种细胞因子。
生理过程。它们的功能障碍与许多疾病有关,如糖尿病,
高血压、心力衰竭和癌症。特定SLC 9成员中的基因突变也
与Angelman综合征样障碍、ADHD、家族性自闭症、癫痫和
男性不育症SLC 9 C1是SLC 9家族的独特成员。与其他SLC 9不同,
其特征在于膜界定的钠-氢交换(NHE)结构域和通常短且
相对非结构化的C-末端可溶性结构域,SLC 9 C1结合了NHE,电压敏感性结构域,
结构域(VSD)和环核苷酸结合结构域(CNBD),通过长的,结构化的
连接子,在单个多肽中。最近的基础实验表明,膜
超极化和环核苷酸的结合增强了通过SLC 9 C1的离子转运。其
独特的设计使得不可能预测这种蛋白质的电压和配体调节是如何进行的。
表现在结构层面。SLC 9 C1表现出精子特异性表达,
对小鼠和人类的精子活力至关重要。精子活力受到以下因素的强烈调节:
膜电压、细胞内cAMP水平和pH的变化以及所有这些刺激影响
SLC 9 C1直接介导离子交换,这使得了解SLC 9 C1的分子机制至关重要。
这种多样性的监管基础。为此,在本提案中,我们将整合单一-
粒子冷冻电子显微镜和重建技术与生化和
电生理学方法探索SLC 9 C1的关键生物物理机制。目标1:
将确定SLC 9 C1的第一个高分辨率结构,并确定关键的相互作用
管理其组织。在目标2中,我们将阐明SLC 9 C1中的结构重排
触发环核苷酸结合,并使用电生理学测试的关键接口的作用
在调节CNBD的调节作用中的作用。在目标3中,我们将确定pH值和渗透率
离子影响SLC 9 C1的结构和功能。这个建议有很强的科学基础
建立在我们严格的初步研究之上它是创新的,因为它将提供一个
新的膜蛋白在不同的构象和测试挑衅性的假设,
转运蛋白的电压和环核苷酸调节机制。获得的见解
将有助于基于结构的药物设计用于治疗男性不育症。它还将
具有广泛的影响的结构和功能机制的SLC 9调控,其
胞质结构域进一步强调了其对人类健康的重要性。
项目成果
期刊论文数量(0)
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科研奖励数量(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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