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Relating protein interaction networks to physiology by systematic mutant analyses

通过系统突变分析将蛋白质相互作用网络与生理学联系起来

基本信息

批准号：
10649444
负责人：
DANIEL N BOLON
金额：
$ 35.18万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649444
关键词：
ATP phosphohydrolase Antineoplastic Agents Biochemical Biophysics Calcineurin Catalytic Domain Cells Client Complex Dependence Development Disease Dominant-Negative Mutation Drug Targeting Drug resistance Fungal Drug Resistance Genes Glucocorticoid Receptor Grant Growth Health Human Individual Libraries Link Malignant Neoplasms Maps Medical Molecular Chaperones Mutation Mycoses Outcome Phosphoric Monoester Hydrolases Phosphotransferases Physiology Point Mutation Positioning Attribute Process Proteins Publishing Reporter Resolution Reverse engineering Role Route Sampling Signal Transduction Signaling Protein Site Sodium Chloride Structure System Technology Therapeutic Variant Work Yeasts biological adaptation to stress combat dominant genetic mutation fitness fungus human disease improved inhibitor insight mutant mutation screening next generation sequencing novel strategies pressure promoter protein protein interaction side effect tool transcription factor

项目摘要

Hsp90 is an essential eukaryotic chaperone that helps to produce and maintain the active state of a select set of substrates or clients that are disproportionately linked to signaling processes including many that promote cancer and the emergence of drug resistance in fungi. For these reasons, inhibitor strategies to manipulate the Hsp90 chaperone system promise many potential therapeutic benefits. Inhibitors targeting the ATPase site of Hsp90 effectively limit the emergence of drug resistance in fungi and show promise as anti-cancer agents. However, ATPase inhibitors block all known functions of Hsp90, leading to undesirable side effects. In our previous work, we generated a comprehensive library of all possible mutations at each of the 709 positions in Hsp90 and quantified the effects of each variant on yeast growth rate as a readout of overall network function integrated over all client proteins. We will build on this work to investigate Hsp90-client interaction mechanism. We will determine how four specific clients are impacted by Hsp90 mutations, which will identify sites on Hsp90 that could be targeted to inhibit specific clients. We will perform deep mutational scanning on specific client proteins to identify the biophysical features that determine Hsp90 dependence. In addition, we have developed a novel approach to quantify the dominant effects of Hsp90 mutations, which we are using as a powerful new route to understand its mechanism of action. Our studies will provide important mechanistic insights into a protein-protein interaction network that is biologically and medically important.

Hsp90是一种重要的真核伴侣蛋白，有助于产生和维持活性状态