Structural characterization of interacting and aggregating cataract-associated crystallins
白内障相关晶状体蛋白相互作用和聚集的结构表征
基本信息
- 批准号:10218184
- 负责人:
- 金额:$ 32.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAgingAmericanBehaviorBiochemicalBiophysicsBlindnessCataractCellsChemicalsComplexCrystalline LensCrystallinsCrystallizationDNA Sequence AlterationDataDegenerative DisorderDepositionDevelopmentDiffusionDiseaseDisease ProgressionElectron MicroscopyEnvironmentExhibitsEyeGene FamilyGene MutationGenesHeterogeneityHumanIndividualKnowledgeLens OpacitiesLightLiquid substanceMagicMapsMeasuresMedicalMembrane LipidsMethodologyMethodsModificationMolecularMolecular ChaperonesMolecular Sieve ChromatographyMolecular StructureMutationNMR SpectroscopyNuclear Magnetic ResonanceOperative Surgical ProceduresOrganellesPathologicPersonsPhasePhysiologicalPopulationPost-Translational Protein ProcessingProcessProteinsRefractive IndicesReportingResearchResolutionRoentgen RaysS-crystallinSamplingScienceSeriesSolubilityStructureStructure-Activity RelationshipSurfaceSurgical complicationSystemTestingVariantVisual impairmentWorkage effectage relatedagedalpha-Crystallinsbiophysical analysisbiophysical propertiescongenital cataractdeamidationearly onsetexperimental studyfiber cellglycationinsightintermolecular interactionlenslens transparencylight scatteringmutantnovelnovel therapeutic interventionnovel therapeuticsoxidationprotein aggregationprotein protein interactionprotein structuresolid statesolid state nuclear magnetic resonance
项目摘要
Project Summary
Cataracts are the leading cause of blindness in the world, with approximately 22 million cases per year. The
disease is caused by protein aggregation in the eye lens, involving its major constituents, the crystallins.
Currently, the only available treatment is surgery, widely used in the developed world. However, access to
surgery is not available to a significant fraction of the world population, and, as with any surgery, complications
may ensue. Therefore, it is important to provide a structural understanding of cataract formation, if novel
therapeutic approaches are to be developed for delaying the onset or slowing the progression of cataracts. While
the congenital form of the disease has been mapped to crystallin gene mutations, the age-related degenerative
disease is believed to involve chemically-modified crystallin proteins. Previously, we investigated the dynamics,
structure and folding of human gD-crystallin mutants that are associated with congenital cataracts. We solved
NMR and X-ray crystal structures of several variants and analyzed their dynamic behavior by solution NMR
spectroscopy. Our aim now is to elucidate the interactions between different crystallins, under physiologically-
relevant high concentrations. We will investigate proteins with modifications that mimic aging and using
congenital cataract-associated mutants. We hypothesize that surface changes that impact the liquid phase
behavior of the crystallin and/or generate aberrant protein-protein interactions contribute to aggregation.
Our studies will not only provide insight into the process of cataract formation but also will shed light on
fundamental questions in protein science. Although biochemical and biophysical studies have provided a detailed
picture of individual crystallin structures and stability, extensive studies are needed to assess the interplay
between different crystallin proteins and, thereby, provide critical data on crystallin structure/function
relationships. For example, the interactions that permit high protein concentrations in lens cells and questions
about which, why, and how certain crystallins interact without aggregation in the normal lens require direct
experimental studies to gain new insights. In addition, several post-translational modifications have been
reported to occur upon lens aging, impacting lens transparency. Whether and how such "aged" crystallins
contribute to protein stability and aggregation is unknown. The proposed research will address these outstanding
issues through biophysical analyses of wild-type, disease-associated, and chemically-modified, “aged”, crystallin
variants. Structural studies by solution and solid-state nuclear magnetic resonance (NMR) spectroscopy, small
angle x-ray scattering (SAXS), and electron microscopy methods will be used to directly investigate different
crystallin mixtures to obtain novel insights into the behavior of normal assemblies involving lens-opacity
associated proteins. Structural details of such assemblies cannot be obtained by any other methodologies.
项目摘要
白内障是世界上致盲的主要原因,每年约有2200万例。的
这种疾病是由眼睛透镜中的蛋白质聚集引起的,包括其主要成分晶状体蛋白。
目前,唯一可用的治疗方法是手术,在发达国家广泛使用。然而,进入
手术对于世界上很大一部分人口来说是不可用的,并且,与任何手术一样,
可能随之而来。因此,重要的是提供白内障形成的结构理解,如果新颖的话,
将开发用于延迟白内障的发作或减缓其进展的治疗方法。而
这种疾病的先天性形式已经被定位为晶体蛋白基因突变,
疾病被认为涉及化学修饰的晶状体蛋白。先前,我们调查了动力学,
与先天性白内障相关的人gD-晶状体蛋白突变体的结构和折叠。我们解决
通过溶液核磁共振和X射线衍射分析了几种变体的晶体结构,并分析了它们的动力学行为
谱我们现在的目标是阐明不同晶体蛋白之间的相互作用,在生理学-
相关高浓度。我们将研究蛋白质的修改,模仿老化和使用
先天性白内障相关突变体我们假设影响液相的表面变化
晶状体蛋白的行为和/或产生异常的蛋白质-蛋白质相互作用有助于聚集。
我们的研究不仅将提供对白内障形成过程的深入了解,
蛋白质科学的基本问题。虽然生物化学和生物物理学研究提供了详细的
单个晶体蛋白结构和稳定性的图片,需要广泛的研究来评估相互作用
不同晶体蛋白质之间的差异,从而提供晶体蛋白结构/功能的关键数据
关系。例如,在透镜细胞中允许高蛋白浓度的相互作用和问题
关于哪些、为什么以及某些晶状体蛋白如何在正常透镜中不聚集地相互作用,需要直接研究
实验研究以获得新的见解。此外,还研究了几种翻译后修饰。
据报道在透镜老化时发生,影响透镜的透明度。这些“老化”晶体蛋白是否以及如何
对蛋白质稳定性和聚集的贡献是未知的。拟议的研究将解决这些悬而未决的问题,
通过对野生型、疾病相关的和化学修饰的“老化”晶状体蛋白的生物物理分析,
变体。通过溶液和固态核磁共振(NMR)光谱进行结构研究,小
角X射线散射(SAXS)和电子显微镜方法将用于直接研究不同的
晶状体蛋白混合物,以获得涉及透镜不透明度的正常组装行为的新见解
相关蛋白质这些组件的结构细节无法通过任何其他方法获得。
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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ANGELA M. GRONENBORN其他文献
ANGELA M. GRONENBORN的其他文献
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{{ truncateString('ANGELA M. GRONENBORN', 18)}}的其他基金
Molecular, Cellular and Behavioral Impact of the R203W PACS1 Syndrome Mutation
R203W PACS1 综合征突变的分子、细胞和行为影响
- 批准号:
10440654 - 财政年份:2022
- 资助金额:
$ 32.51万 - 项目类别:
Pittsburgh Center for HIV Protein Interactions (PCHPI)
匹兹堡 HIV 蛋白质相互作用中心 (PCHPI)
- 批准号:
10506945 - 财政年份:2022
- 资助金额:
$ 32.51万 - 项目类别:
Pittsburgh Center for HIV Protein Interactions (PCHPI)
匹兹堡 HIV 蛋白质相互作用中心 (PCHPI)
- 批准号:
10653242 - 财政年份:2022
- 资助金额:
$ 32.51万 - 项目类别:
Molecular, Cellular and Behavioral Impact of the R203W PACS1 Syndrome Mutation
R203W PACS1 综合征突变的分子、细胞和行为影响
- 批准号:
10612914 - 财政年份:2022
- 资助金额:
$ 32.51万 - 项目类别:
Structural characterization of interacting and aggregating cataract-associated crystallins
白内障相关晶状体蛋白相互作用和聚集的结构表征
- 批准号:
10463640 - 财政年份:2019
- 资助金额:
$ 32.51万 - 项目类别:
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