Integrative NMR and biophysical studies of fibrillar protein assemblies in health and disease
Integrative NMR and biophysical studies of fibrillar protein assemblies in health and disease
批准号:
10392359
负责人:
JEAN S BAUM
金额:
$57.07万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-01 至 2025-04-30
关键词:
AddressAmyloidArchitectureAtomic Force MicroscopyBindingBinding SitesBiologicalBiologyBiophysicsCell physiologyCellsCellular AssayCollagenCollagen FibrilComplexComputing MethodologiesConnective Tissue DiseasesCryoelectron MicroscopyDefectDiseaseDisease ProgressionExtracellular MatrixHealthHomeostasisHourInheritedIntegrinsInterventionLightLinkMolecularMolecular ConformationMotionMutationNMR SpectroscopyNatureNeurodegenerative DisordersOsteogenesis ImperfectaParkinson DiseasePathologicPlatelet aggregationPlayPropertyProteinsProtocols documentationRoleSpecificityStructureSurfaceSurface PropertiesSystemTechniquesTherapeuticTimealpha synucleinbiological systemsbiophysical analysisbiophysical toolsdesignmonomernanoscalenovelnovel therapeutic interventionself assemblysolid state nuclear magnetic resonancesynucleinopathy
中文摘要
摘要
蛋白质自组装成结构化原纤维在生物学中起着功能和功能失调的作用。我们
研究两类原纤维形成蛋白:胶原蛋白,一种与胶原蛋白形成重要相互作用的原纤维。
许多蛋白质和细胞外基质成分的适当细胞功能和α-突触核蛋白(αS),
自组装成低聚物和原纤维的内在无序蛋白质,
突触核蛋白病,如帕金森病。虽然在这两种情况下,原纤维通常被认为是刚性的,
相当惰性的实体,我们最近发现了构象动力学,深刻影响其原子-
到纳米级的性能。尽管这些纤维蛋白的重要性,纤维蛋白的分子决定因素,
蛋白质相互作用及其对健康和疾病的影响仍然没有答案。因此,总体目标
这个提议的一个重要目的是了解分子运动和表面性质如何调节蛋白质相互作用
在不同的组装阶段(单体,低聚物,原纤维),空间范围(原子到纳米级),和时间
方案(皮秒至小时),以促进正常的稳态或病理疾病状态。的统一
这项提案的主题是,我们正在开发的关键技术和必要的原纤维协议,
表征,认识到这些系统的构象可塑性和不同的相互作用。我们使用
多方面的方法集成解决方案和固态核磁共振光谱,原子
力显微镜,冷冻电子显微镜,计算方法,并将这些与细胞实验联系起来。
我们正在解决胶原纤维如何识别其结合伴侣的问题(我们特别关注
整合素,一种参与血小板聚集的关键蛋白质),尽管事实上许多结合位点隐藏在
复杂的胶原纤维结构。除了健康纤维的结构/功能,我们还将研究
Gly β X突变对遗传性结缔组织病如成骨不全(脆性)影响
骨疾病),并首次可视化这些缺陷如何影响原纤维组装,结构和
功能虽然是一个非常不同的生物系统,但我们对αS提出了类似的原纤维相互作用问题:
细胞增殖和通过原纤维模板接种内源性αS单体增加了原纤维的数量
并且是疾病进展的主要因素之一。这种相互作用机制还不清楚,我们
将首先从原子到纳米尺度表征淀粉样蛋白表面,然后
使单体与它们的相互作用可视化。结果将揭示的性质和特异性,
胶原蛋白和αS相互作用,疾病相关胶原蛋白突变的生物物理学和生物学影响,
以及病理性细胞间增殖和接种αS聚集体的机制。阐释性小说
相互作用机制将有助于设计新的治疗策略来拯救受损的胶原蛋白
相互作用或病理性αS聚集在毁灭性的神经退行性疾病。
英文摘要
Abstract
Protein self-assembly into structured fibrils plays both functional and dysfunctional roles in biology. We are
investigating two classes of fibril forming proteins: collagen, a fibril that forms essential interactions with
numerous proteins and extracellular matrix components for proper cellular function and α-synuclein (αS), an
intrinsically disordered protein that self-assembles into oligomers and fibrils that are associated with debilitating
synucleinopathies, such as Parkinson’s Disease. While in both cases, fibrils are often thought of as rigid,
rather inert, entities, we have recently discovered conformational dynamics that profoundly impact their atomic-
to-nano scale properties. Despite the importance of these fibrillar proteins, the molecular determinants of fibril-
protein interactions and their impact in health and disease remain unanswered. Thus, the overarching objective
of this proposal is to understand how molecular motions and surface properties modulate protein interactions
at different assembly stages (monomer, oligomer, fibril), spatial extent (atomic to nanoscale), and temporal
regime (picosecond to hours) to promote normal homeostasis or pathological disease states. The unifying
theme of this proposal is that we are developing the key techniques and protocols necessary for fibril
characterization that recognize the conformational plasticity and diverse interactions of these systems. We use
a multifaceted approach integrating solution and solid-state nuclear magnetic resonance spectroscopy, atomic
force microscopy, cryo-electron microscopy, computational methods, and link these to cellular experimentation.
We are addressing the question of how collagen fibrils recognize their binding partners (we focus in particular
on integrin, a key protein involved in platelet aggregation) despite the fact that many binding sites are hidden in
the complex collagen fibril architecture. Beyond structure/function in healthy fibrils, we will investigate the
impact of GlyX mutations in hereditary connective tissue disease such as Osteogenesis Imperfecta (brittle
bone disease) and visualize for the first time how these defects impact on fibril assembly, structure and
function. Although a very different biological system, we raise similar fibril interaction questions for αS: cell-to-
cell propagation and templated seeding of endogenous αS monomers by fibrils increases the number of fibrils
and is one of the primary factors in disease progression. This interaction mechanism is not understood and we
will investigate this by first characterizing amyloid surfaces from the atomic to the nano-scale and then
visualizing the interactions of the monomers with them. Results will shed light on the nature and specificity of
collagen and αS interactions, the biophysical and biological impact of disease-affiliated collagen mutations,
and mechanisms of pathological cell-to-cell propagation and seeding of αS aggregates. Elucidating novel
interaction mechanisms will aid in design of new therapeutic strategies to rescue compromised collagen
interactions or pathological αS aggregation in devastating neurodegenerative disease.
期刊论文(0)
专著(0)
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会议论文
The Protein Aggregation Conference: Exploring Rugged Landscapes
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批准号:10681615
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项目类别:
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资助金额:$1.5万
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财政年份:2023
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负责人:JEAN S BAUM
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依托单位:
Integrative NMR and biophysical studies of fibrillar protein assemblies in health and disease
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批准号:10613473
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项目类别:
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资助金额:$57.3万
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财政年份:2020
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依托单位:
Rutgers Helium Recovery System for High Field NMR
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批准号:10170724
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NMR Based Studies of Alpha-Synuclein Aggregation and Inhibition
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批准号:9527263
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项目类别:
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资助金额:$4.7万
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财政年份:2015
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负责人:JEAN S BAUM
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依托单位:
Experiments & Computations to Find Aggregation-Prone Ensembles of Alpha-Synuclein
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批准号:7945284
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项目类别:
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资助金额:$30.07万
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财政年份:2009
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负责人:JEAN S BAUM
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依托单位:
NMR Studies of Triple helical Peptides
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批准号:7933138
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项目类别:
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资助金额:$27.04万
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财政年份:2009
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负责人:JEAN S BAUM
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依托单位:
NMR STUDIES OF TRIPLE HELICAL PEPTIDES
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批准号:2183057
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项目类别:
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资助金额:$17.57万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR studies of collagen model peptides and their interactions with collagen recep
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批准号:8518349
-
项目类别:
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资助金额:$29.51万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR studies of collagen model peptides and their interactions with collagen recep
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批准号:8667455
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项目类别:
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资助金额:$30.71万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR STUDIES OF TRIPLE HELICAL PEPTIDES
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批准号:6625083
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项目类别:
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资助金额:$21.52万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR STUDIES OF TRIPLE HELICAL PEPTIDES
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批准号:2459420
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项目类别:
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资助金额:$17.63万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR STUDIES OF TRIPLE HELICAL PEPTIDES
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批准号:6018822
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项目类别:
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资助金额:$18.68万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR studies of collagen model peptides and their interactions with collagen recep
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批准号:8387900
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项目类别:
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资助金额:$29.32万
-
财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR STUDIES OF TRIPLE HELICAL PEPTIDES
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批准号:2749878
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项目类别:
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资助金额:$18.15万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR APPROACHES TO THE PROTEIN FOLDING PROBLEM
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批准号:3468300
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项目类别:
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资助金额:$10.36万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR Studies of Triple helical Peptides
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批准号:7626020
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项目类别:
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资助金额:$26.18万
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财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR studies of collagen model peptides and their interactions with collagen recep
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批准号:8533502
-
项目类别:
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资助金额:$2.98万
-
财政年份:1991
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负责人:JEAN S BAUM
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依托单位:
NMR Studies of Triple helical Peptides
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批准号:7321964
-
项目类别:
-
资助金额:$28.43万
-
财政年份:1991
-
负责人:JEAN S BAUM
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依托单位:
NMR Studies of Triple helical Peptides
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批准号:7851082
-
项目类别:
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资助金额:$25.9万
-
财政年份:1991
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负责人:JEAN S BAUM
-
依托单位:
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