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Bioinorganic Explorations of Host-defense Proteins

宿主防御蛋白的生物无机探索

基本信息

批准号：
10662538
负责人：
ELIZABETH M NOLAN
金额：
$ 31.44万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662538
关键词：
Address Anti-Bacterial Agents Area Bacterial Physiology Binding Biochemical Biological Biophysics Case Study Cell physiology Chemistry Clinical Research Complex Development Diagnostic Disease Disulfides Environment Epithelial Cells Extracellular Space Funding Goals Growth Homeostasis Host Defense Human Human Pathology Immune Infection Infection prevention Inflammation Inflammatory Innate Immune Response Innate Immune System Intestines Invaded Investigation Ions Laboratories Leukocyte L1 Antigen Complex Link Metals Methionine Modeling Molecular Mus Nutrient Nutrient availability Nutritional Immunity Organism Outcome Pathology Peptide Hydrolases Physiology Play Post-Translational Protein Processing Property Proteins Research Resistance Role Rosaniline Dyes S100A8 gene S100A9 gene Site Starvation Structure Testing Therapeutic Transition Elements Urinary tract infection Uropathogenic E. coli Work biophysical properties design disulfide bond expectation extracellular host-microbe interactions human disease in vivo insight microbial molecular modeling neutrophil novel diagnostics oxidation pathogen pathogenic Escherichia coli pathogenic bacteria pathogenic fungus pathogenic microbe prevent response uptake

项目摘要

PROJECT SUMMARY The overarching goal of this renewal application is to elucidate the molecular basis for how human calprotectin (CP, S100A8/S100A9 oligomer) functions in the metal-withholding innate immune response, and to evaluate its impact on the physiology of uropathogenic Escherichia coli (UPEC), which cause the majority of urinary tract infections in humans. Transition metals are essential nutrients for all organisms, and the availability of these nutrients plays a critical role during microbial infection. Consequently, the human innate immune system launches a metal-withholding response and deploys metal-sequestering host-defense proteins into the extracellular space to limit metal availability and hinder pathogen growth. CP is an abundant and functionally versatile metal-withholding protein; it sequesters multiple metal nutrients including Mn(II), Fe(II), Ni(II) and Zn(II). Recent studies by our laboratory and others provide compelling evidence that the molecular speciation of extracellular CP is a heterogenous ensemble of different species that arises from different metal-bound forms as well as oxidative post-translational modifications. We hypothesize that this complex molecular speciation of CP, including the occurrence of methionine oxidation and disulfide bonding, has profound consequences for its extracellular function and lifetime. Recent studies by our laboratory and others also demonstrate that CP is a Cu-withholding protein. We hypothesize that CP sequesters both Cu(II) and Cu(I) and that this function impacts the physiology and metal homeostasis in diverse bacterial pathogens including UPEC. In Aim 1, we will examine disulfide bond formation within and between CP heterodimers, the biophysical properties of these disulfide-linked species, and their ability to sequester metals from bacterial pathogens. In Aim 2, we will evaluate the Cu(II/I)-binding properties of CP and the consequences of multi- metal sequestration by CP on UPEC as a case study. We expect that these investigations will advance the molecular model for how CP contributes to the metal-sequestering innate immune response, underscore the importance of considering CP species that result from oxidative posttranslational modification, and elucidate the molecular basis for Cu withholding by CP. Moreover, we expect that our studies of the interplay of CP and UPEC will provide new insight into how the host and pathogen compete for Cu and other nutrient metals. We further expect that the outcomes of this initiative may guide the design and development of novel diagnostic, preventative and therapeutic approaches for microbial infections and other pathologies such as inflammatory diseases that involve CP.

项目总结这一更新应用的首要目标是阐明人类钙化保护蛋白的分子基础 (CP，S100A8/S100A9寡聚体)在金属抑制的先天免疫反应中的作用，并评价其尿路致病性大肠埃希菌对生理学的影响对人类的感染。过渡金属是所有生物体必不可少的营养物质，而这些营养物质的可用性营养物质在微生物感染过程中起着至关重要的作用。因此，人类的先天免疫系统启动抑制金属的反应并将隔离金属的宿主防御蛋白部署到限制金属供应和阻碍病原体生长的细胞外空间。CP是一个内容丰富、功能齐全的多功能金属抑制蛋白；它隔离多种金属营养物质，包括锰(II)、铁(II)、镍(II)和锌(II)。我们实验室和其他实验室最近的研究提供了令人信服的证据，证明分子物种形成胞外CP是不同物种的异质集合，来自不同的金属结合形式以及氧化翻译后修饰。我们假设这个复杂的分子 CP的形态形成，包括蛋氨酸氧化和二硫键的发生，具有深远的意义对其细胞外功能和寿命的影响。我们实验室和其他实验室最近的研究也证明CP是一种含铜蛋白。我们假设CP对铜(II)和铜(I)都有隔离作用这一功能影响不同细菌病原体的生理和金属动态平衡，包括 UPEC。在目标1中，我们将研究CP杂二聚体内部和之间的二硫键的形成，这些二硫键连接物种的生物物理性质及其从细菌中隔离金属的能力病原体。在目标2中，我们将评估CP与铜(II/I)结合的性质以及多重结合的后果。以UPEC上CP对金属的封存为例。我们预计这些调查将推进 CP如何促进金属隔离的先天免疫反应的分子模型，强调考虑氧化翻译后修饰产生的CP物种的重要性，并阐明 CP抑制铜的分子基础。此外，我们预计，我们对CP和Cp相互作用的研究 UPEC将为宿主和病原体如何竞争铜和其他营养金属提供新的见解。我们进一步期望这一倡议的结果可以指导设计和开发新的诊断方法，预防和治疗微生物感染和其他病理疾病的方法，如炎症涉及CP的疾病。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transition Metal Sequestration by the Host-Defense Protein Calprotectin.

DOI：
10.1146/annurev-biochem-062917-012312
发表时间：
2018-06-20
期刊：
Annual review of biochemistry
影响因子：
16.6
作者：
Zygiel EM;Nolan EM
通讯作者：
Nolan EM

Zinc sequestration by human calprotectin facilitates manganese binding to the bacterial solute-binding proteins PsaA and MntC.

DOI：
10.1093/mtomcs/mfac001
发表时间：
2022-03-10
期刊：
Metallomics : integrated biometal science
影响因子：
0
作者：
Rosen T;Hadley RC;Bozzi AT;Ocampo D;Shearer J;Nolan EM
通讯作者：
Nolan EM

S100A12 promotes Mn(II) binding to pneumococcal PsaA and staphylococcal MntC by Zn(II) sequestration.

DOI：
10.1016/j.jinorgbio.2022.111862
发表时间：
2022-08
期刊：
JOURNAL OF INORGANIC BIOCHEMISTRY
影响因子：
3.9
作者：
Rosen, Tomer;Nolan, Elizabeth M.
通讯作者：
Nolan, Elizabeth M.

Molecular Basis of Ca(II)-Induced Tetramerization and Transition-Metal Sequestration in Human Calprotectin.

DOI：
10.1021/jacs.1c06402
发表时间：
2021-11-03
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Silvers R;Stephan JR;Griffin RG;Nolan EM
通讯作者：
Nolan EM

Biophysical Examination of the Calcium-Modulated Nickel-Binding Properties of Human Calprotectin Reveals Conformational Change in the EF-Hand Domains and His3Asp Site.

对人钙卫蛋白的钙调节镍结合特性的生物物理检查揭示了 EF-Hand 结构域和 His3Asp 位点的构象变化。

DOI：
10.1021/acs.biochem.8b00415
发表时间：
2018
期刊：
Biochemistry
影响因子：
2.9
作者：
Nakashige,ToshikiG;Bowman,SarahEJ;Zygiel,EmilyM;Drennan,CatherineL;Nolan,ElizabethM
通讯作者：
Nolan,ElizabethM