Research Initiation Award: Revealing the Structural Basis for Calprotectin-RAGE Signaling Axis

研究启动奖:揭示钙卫蛋白-RAGE信号轴的结构基础

基本信息

  • 批准号:
    1400969
  • 负责人:
  • 金额:
    $ 20万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2017-07-31
  • 项目状态:
    已结题

项目摘要

Research Initiation Awards (RIAs) provide support for junior faculty at Historically Black Colleges and Universities (HBCUs) who are starting to build a research program, as well as for mid-career faculty who need to re-direct and re-build a research program. It is expected that the award helps to further the faculty member's research capability and effectiveness, improves research and teaching at the researcher's home institution, and involves undergraduate students in research experiences.Fisk University's RIA project utilizes well established experimental structural biology and biophysical techniques to establish a transformative new paradigm for the mechanism of regulation of protein-protein interactions in signal transduction. The results will have a significant impact on the fields of structural biology and signal transduction. Characterization of the CP-RAGE VC1 complex at atomic-resolution represents a significant advance forward for S100 and RAGE biology. This would be the first high resolution structure of the RAGE ligand binding extracellular domain in complex with a protein, and one of few S100 proteins in complex with its cognate binding partner. Moreover, the approaches employed in this investigation represent a general approach to addressing mechanism of receptor activation.This research addresses a critical gap in this knowledge by employing high resolution structural studies to reveal the atomic resolution details of the CP-RAGE complex. RAGE is a transmembrane protein comprised of three extracellular immunoglobulin domains (V, C1, and C2), a single transmembrane helix (TM), and a short intracellular peptide (IC). Like many other single pass receptors, activation is hypothesized to proceed through an oligomerization based conformational rearrangement that occurs during ligand binding. The outcomes of the research initiation project will further the diversification of the STEM workforce by providing unparalleled training to students that have been historically underrepresented in STEM. This interdisciplinary program provides integrated research training and didactic coursework at the interface of chemistry, biology, and physics illustrating to students the impact of transdisciplinary research and high impact discovery. Undergraduate students will present their findings at regional and national meetings and will co-author peer-reviewed publications. As an NSF Experimental Program to Stimulate Competitive Research (EPSCoR) jurisdiction, the project will build research capability and capacity in the state as well as within this minority-serving institution. Page AThis research initiation award proposes to understand the molecular basis of interactionsbetween the S100 calcium binding protein calprotectin (CP) and the receptor for advanced glycationendproducts (RAGE). CP binding to RAGE results in activation of the transcription factor NFkB,a molecule which plays a key role in inflammation. Despite the importance of this signalingaxis, little is known about the structural details of the protein-protein interactions whichgovern CP-RAGE binding. This proposal addresses a critical gap in this knowledge by employinghigh resolution structural studies to reveal the atomic resolution details of the CP-RAGEcomplex. RAGE is a transmembrane protein comprised of three extracellular immunoglobulin domains(V, C1, and C2), a single transmembrane helix (TM), and a short intracellular peptide (IC).Like many other single pass receptors, activation is hypothesized to proceed through an oligomerizationbased conformational rearrangement that occurs during ligand binding. The focus of this proposalis on the V and C1 extracellular domains of RAGE (RAGE VC1) and how they contribute to CPbinding and/or oligomerization during receptor activation. In order to address these questions,two complementary but independent objectives are proposed: Objective 1) Define the molecularbasis for CP interaction with RAGE. Nuclear magnetic resonance spectroscopy (NMR) will beused to identify amino acid residues in CP and RAGE VC1 that are critical for binding. TheNMR studies will be validated and used to guide strategies to create mutants in CP that aredefective in RAGE binding as assayed by isothermal titration calorimetry. Objective 2) Characterizethe oligomerization state of the CP-RAGE VC1 complex. X-ray crystallography will be used todetermine the structure of the CP-RAGE VC1 complex. This structure will reveal high resolutiondetails of the interaction between CP and RAGE, as well as interactions that define the oligomerizationbehavior of the overall complex.Intellectual Merit :The research initiation award utilizes well established experimental structural biology andbiophysical techniques to establish a transformative new paradigm for the mechanism of regulationof protein-protein interactions in signal transduction. The results will have a significantimpact on the fields of structural biology and signal transduction. Characterization of theCP-RAGE VC1 complex at atomic-resolution represents a significant advance forward for S100and RAGE biology. This would be the first high resolution structure of the RAGE ligand bindingextracellular domain in complex with a protein, and one of few S100 proteins in complex withits cognate binding partner. Moreover, the approaches employed in this proposal representa general approach to addressing mechanism of receptor activation.Broader Impacts :The outcomes of this research initiation award will further the diversification of the STEMworkforce by providing unparalleled training to students that have been traditionally underrepresentedin STEM. This interdisciplinary program provides integrated research training and didacticcoursework at the interface of chemistry, biology, and physics -illustrating to students theimpact of transdisciplinary research and high impact discovery. Undergraduate students willpresent their findings at regional and national meetings, and will co-author peer-reviewedpublications. Enhancements in research and curriculum infrastructure at Fisk University providedby this RIA will contribute to recruitment and retention of minorities in STEM disciplines,resulting in the development of early career scientists into discoverers and leaders in academicand research careers.
研究启动奖(RIAs)为传统黑人学院和大学(HBCUs)中开始建立研究项目的初级教师提供支持,也为需要重新指导和重建研究项目的职业中期教师提供支持。期望该奖项有助于进一步提高教师的研究能力和效率,改善研究人员所在机构的研究和教学,并使本科生参与研究经验。菲斯克大学的RIA项目利用成熟的实验结构生物学和生物物理技术,为信号转导中蛋白质-蛋白质相互作用的调节机制建立了一个变革的新范式。这一结果将对结构生物学和信号转导领域产生重大影响。在原子分辨率上表征CP-RAGE VC1复合物代表了S100和RAGE生物学的重大进展。这将是RAGE配体结合细胞外结构域与蛋白质复合物的第一个高分辨率结构,也是为数不多的S100蛋白与其同源结合伙伴的复合物之一。此外,本研究中采用的方法代表了解决受体激活机制的一般方法。本研究通过采用高分辨率结构研究来揭示CP-RAGE复合物的原子分辨率细节,解决了这方面知识的关键空白。RAGE是一种跨膜蛋白,由三个细胞外免疫球蛋白结构域(V、C1和C2)、一个单跨膜螺旋结构域(TM)和一个短胞内肽(IC)组成。像许多其他单通道受体一样,激活被假设通过在配体结合期间发生的基于寡聚化的构象重排进行。研究启动项目的成果将通过为历史上在STEM中代表性不足的学生提供无与伦比的培训,进一步促进STEM劳动力的多样化。这个跨学科的项目提供综合的研究培训和教学课程,在化学、生物学和物理学的界面上,向学生展示跨学科研究和高影响力发现的影响。本科生将在地区和国家会议上展示他们的发现,并将共同撰写同行评审的出版物。作为美国国家科学基金会刺激竞争性研究(EPSCoR)管辖权的实验计划,该项目将在该州以及这个少数民族服务机构内建立研究能力和能力。该研究启动奖旨在了解S100钙结合蛋白钙保护蛋白(CP)与晚期糖基化终产物受体(RAGE)之间相互作用的分子基础。CP与RAGE结合导致转录因子NFkB的激活,NFkB是炎症中起关键作用的分子。尽管这条信号轴很重要,但人们对控制CP-RAGE结合的蛋白质-蛋白质相互作用的结构细节知之甚少。本提案通过采用高分辨率结构研究来揭示CP-RAGEcomplex的原子分辨率细节,解决了这方面知识的关键空白。RAGE是一种跨膜蛋白,由三个细胞外免疫球蛋白结构域(V、C1和C2)、一个单跨膜螺旋结构域(TM)和一个短胞内肽(IC)组成。像许多其他单通道受体一样,激活被假设通过在配体结合期间发生的基于寡聚化的构象重排进行。本文的重点是RAGE的V和C1胞外结构域(RAGE VC1)以及它们在受体激活过程中如何参与CPbinding和/或寡聚化。为了解决这些问题,提出了两个互补但独立的目标:目标1)确定CP与RAGE相互作用的分子基础。核磁共振波谱(NMR)将用于鉴定CP和RAGE VC1中对结合至关重要的氨基酸残基。mr研究将被验证,并用于指导通过等温滴定量热法检测RAGE结合缺陷的CP突变体的创建策略。目的2)表征CP-RAGE VC1复合物的寡聚化状态。x射线晶体学将用于确定CP-RAGE VC1配合物的结构。该结构将揭示CP和RAGE之间相互作用的高分辨率细节,以及定义整个配合物的寡聚化行为的相互作用。智力奖励:研究启动奖利用成熟的实验结构生物学和生物物理技术,为信号转导中蛋白质-蛋白质相互作用的调节机制建立了一个变革性的新范式。研究结果将对结构生物学和信号转导领域产生重要影响。在原子分辨率上表征ccp -RAGE VC1复合物代表了s100和RAGE生物学的重大进展。这将是RAGE配体结合细胞外结构域与蛋白质复合物的第一个高分辨率结构,也是为数不多的与同源结合伙伴的S100蛋白复合物之一。此外,本提案中采用的方法代表了解决受体激活机制的一般方法。更广泛的影响:这项研究启动奖的结果将通过为传统上在STEM中代表性不足的学生提供无与伦比的培训,进一步促进STEM劳动力的多样化。这个跨学科的项目提供综合的研究培训和教学课程,在化学,生物学和物理学的界面-向学生展示跨学科研究和高影响力发现的影响。本科生将在地区和国家会议上展示他们的发现,并将共同撰写同行评审的出版物。该RIA提供的对菲斯克大学研究和课程基础设施的加强将有助于STEM学科的少数民族的招聘和保留,从而使早期职业科学家发展成为学术研究事业的发现者和领导者。

项目成果

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Steven Damo其他文献

The thermodynamic stability and misfolding of S100A12
  • DOI:
    10.1016/j.bpj.2023.11.2956
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Karly B. Serrano;Rekha Pattanayek;Velia Garcia;Nicole Fana Brito;Jennifer Gaddy;Steven Damo
  • 通讯作者:
    Steven Damo
3D reconstruction shows mouse skeletal muscle may decline in function across aging due to the MICOS complex
  • DOI:
    10.1016/j.bpj.2022.11.2874
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Kit Neikirk;Zer Vue;Edgar Garza-Lopez;Larry Vang;Amber Crabtree;Heather Beasley;Andrea Marshall;Steven Damo;Antentor O. Hinton
  • 通讯作者:
    Antentor O. Hinton
Exploring metal binding induced conformational dynamics of S100A12
  • DOI:
    10.1016/j.bpj.2023.11.396
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Nicole Fana Brito;Velia Garcia;Karly B. Serrano;Antentor O. Hinton;Jennifer A. Gaddy;Steven Damo
  • 通讯作者:
    Steven Damo

Steven Damo的其他文献

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{{ truncateString('Steven Damo', 18)}}的其他基金

Research Initiation Award: Uncovering the Role of Germline-Specific MAGE-B2 Protein in Maintenance of Cellular Identity
研究启动奖:揭示种系特异性 MAGE-B2 蛋白在维持细胞身份中的作用
  • 批准号:
    1764201
  • 财政年份:
    2018
  • 资助金额:
    $ 20万
  • 项目类别:
    Standard Grant

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    2023
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研究启动奖:利用人工智能能力实施下一代物联网生态系统
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Research Initiation Award: Exploring Class A G-Protein Coupled Receptors (GPCRs)-Ligand Interaction through Machine Learning Approaches
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  • 资助金额:
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