Photoreceptor Phosphodiesterase Regulation
光感受器磷酸二酯酶调节
基本信息
- 批准号:10346165
- 负责人:
- 金额:$ 37.23万
- 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:2022-09-30 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Allosteric RegulationArchitectureBindingBlindnessCatalytic DomainCodeCommunicationComplexCone dystrophyCoupledDNA Sequence AlterationDefectDevelopmentDiseaseDockingEnzyme ActivationEnzymesEtiologyEventGTP BindingGTP-Binding ProteinsGenesGoalsGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHeterotrimeric GTP-Binding ProteinsInheritedLightLightingLinkMediatingMissionModelingMolecularMolecular ConformationMolecular TargetMultienzyme ComplexesMutationNational Eye InstituteNight BlindnessOutcomes ResearchPathogenicityPathway interactionsPhotoreceptorsPhototransductionProcessProteinsRecoveryRegulationResearchRetinaRetinal ConeRetinal DegenerationRetinal DiseasesRetinal DystrophyRetinitis PigmentosaRodSignal PathwaySignal TransductionSiteSpeedTherapeutic InterventionTransducinVertebrate PhotoreceptorsVision DisordersVisualWorkachromatopsiaalpha Subunit Transducinbaseclinically significantdimerdisease-causing mutationenzyme activitynext generation sequencingpersonalized therapeuticphosphoric diester hydrolasephotoactivationprogramsprotein Bretinal rods
项目摘要
PROJECT SUMMARY/ABSTRACT
Photoreceptor phosphodiesterase (PDE6) is the central enzyme of the visual signaling pathway. Precise
regulation of its activation and deactivation is essential for the speed, sensitivity, and recovery of rod and cone
photoreceptors to illumination. Inherited mutations in rod and cone PDE6 genes have been linked in a variety
of retinal diseases, including retinitis pigmentosa, congenital stationary night blindness, and cone dystrophy.
Next-generation sequencing is identifying a growing number of mutations in PDE6 genes, the large majority of
which remain of uncertain clinical significance. Even less is known about the molecular etiology of retinal
disease-causing mutations. Rod PDE6 consists of two catalytic subunits whose activity is inhibited in the dark-
adapted state by binding of two identical γ-subunits (Pγ). Upon light-induced activation of the visual signaling
pathway, PDE6 activity is stimulated by binding of the heterotrimeric G-protein, transducin. The lifetime of light-
activated PDE6 is precisely controlled by the rate at which the transducin hydrolyzes its bound GTP, a process
controlled by RGS9-1 (Regulator of G-protein Signaling9-1). While the proteins involved in regulation of PDE6
during phototransduction have been identified, the molecular sequence of events in which PDE6 dynamically
interacts with its binding partners--as well as its allosteric regulation--during PDE6 activation and deactivation
remain poorly understood. Until we understand the mechanistic basis of PDE6 regulation during normal
phototransduction, we will be hampered in developing therapeutic interventions for those diseases arising from
defects in PDE6 or its binding partners that result in retinal degenerative diseases and visual disorders.
The overall objective of this application is to understand the sequence of events accompanying PDE6
activation by transducin and its subsequent inactivation by RGS9-1 and other proteins during recovery of
PDE6 to its dark-adapted state. Our experimental plan is based on the hypothesis that the inhibitory Pγ subunit
of PDE6 is the “master regulator” responsible for mediating multiple allosteric interactions that occur within the
PDE6 catalytic dimer, as well as with the transducin α-subunit and RGS9-1. We propose two specific aims that
will (1) delineate the sequence of binding interactions between transducin α-subunits and PDE6 catalytic and
inhibitory Pγ subunits to provide a comprehensive model of rod PDE6 activation, and (2) determine the
molecular architecture of the PDE6 inactivation complex upon RGS9-1 binding and the structural
rearrangements of the Pγ subunit that accelerate termination of activated PDE6. The outcomes of this
research advance the goals of the Retinal Diseases Program at the National Eye Institute by enhancing our
ability to predict the pathogenicity of mutations in phototransduction proteins, thereby enabling development of
personalized therapeutic interventions for retinal diseases resulting from dysregulation of the visual signaling
pathway in rod and cone photoreceptor cells of the retina.
项目总结/摘要
光感受器磷酸二酯酶(PDE 6)是视觉信号通路的中心酶。精确
调节其激活和去激活对于杆和锥的速度、灵敏度和恢复是至关重要的
光感受器对光照的反应视杆细胞和视锥细胞PDE 6基因的遗传突变与多种
视网膜疾病,包括视网膜色素变性,先天性静止性夜盲症和视锥细胞营养不良。
下一代测序正在识别PDE 6基因中越来越多的突变,
其临床意义仍不确定。甚至对视网膜病变的分子病因学知之甚少,
致病突变杆PDE 6由两个催化亚基组成,其活性在黑暗中被抑制-
通过结合两个相同的γ-亚基(Pγ)的适应状态。在光诱导的视觉信号激活后,
在PDE 6通路中,PDE 6活性通过异源三聚体G蛋白转导素的结合来刺激。光的寿命-
激活的PDE 6是由转导蛋白水解其结合的GTP的速率精确控制的,
RGS9-1(Regulator of G-protein Signaling9-1)虽然参与调节PDE 6的蛋白质
在光转导过程中,已经确定了PDE 6动态变化的分子序列,
在PDE 6激活和失活过程中,
人们对它了解仍然很少。直到我们了解正常情况下PDE 6调节的机制基础,
光转导,我们将受到阻碍,在开发治疗干预措施,为这些疾病引起的
PDE 6或其结合配偶体的缺陷导致视网膜变性疾病和视觉障碍。
本申请的总体目标是了解伴随PDE 6的事件序列
在恢复过程中,通过转导蛋白激活并随后通过RGS 9 -1和其他蛋白失活,
PDE 6进入暗适应状态。我们的实验计划是基于这样的假设,即抑制性Pγ亚基
PDE 6是负责介导多种变构相互作用的“主调节因子”,
PDE 6催化二聚体,以及与转导素α-亚基和RGS 9 -1。我们提出两个具体目标,
将(1)描述转导素α亚基和PDE 6催化剂之间结合相互作用的顺序,
抑制性Pγ亚基,以提供视杆细胞PDE 6激活的综合模型,以及(2)确定
RGS 9 -1结合后PDE 6失活复合物的分子结构和结构
Pγ亚基的重排加速了活化的PDE 6的终止。这一过程的结果
研究通过提高我们的视网膜疾病计划的目标在国家眼科研究所
预测光转导蛋白突变致病性的能力,从而使开发
针对由视觉信号失调引起的视网膜疾病的个性化治疗干预
视网膜的视杆和视锥感光细胞中的信号通路。
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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{{ truncateString('Rick H Cote', 18)}}的其他基金
SARS-CoV-2 whole genome sequencing from large-scale campus testing and state-wide communities in NH--Center of Integrated Biomedical and Bioengineering Research (CIBBR)
来自新罕布什尔州大规模校园测试和全州社区的 SARS-CoV-2 全基因组测序——综合生物医学和生物工程研究中心 (CIBBR)
- 批准号:
10381231 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
Center of Integrated Biomedical and Bioengineering Research (CIBBR)
综合生物医学与生物工程研究中心(CIBBR)
- 批准号:
10179412 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
Targeting STAT3 in Ovarian Cancer- Center for Integrated Biomedical and Bioengineering (CIBBR)
卵巢癌中的 STAT3 靶向治疗 - 综合生物医学和生物工程中心 (CIBBR)
- 批准号:
10395120 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
SARS-CoV-2 whole genome sequencing from large-scale campus testing and state-wide communities in NH
来自新罕布什尔州大规模校园测试和全州社区的 SARS-CoV-2 全基因组测序
- 批准号:
10595370 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
Center of Integrated Biomedical and Bioengineering Research (CIBBR)
综合生物医学与生物工程研究中心(CIBBR)
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10714950 - 财政年份:2017
- 资助金额:
$ 37.23万 - 项目类别:
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