权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Structure, Function and Regulation of Human O-GlcNAcase

人O-GlcNAcase的结构、功能和调控

基本信息

批准号：
10006578
负责人：
Jiaoyang Jiang
金额：
$ 28.96万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2017-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006578
关键词：
Affect Alzheimer&apos s Disease Apoptosis Apoptotic Binding Biological Process Biology Catalytic Domain Cell Death Cell Survival Cells Cessation of life Cleaved cell Complex Couples Coupling Crystallization Development Diabetes Mellitus Disease Distant Enzymes Equilibrium Family Foundations Glycopeptides Glycoproteins Glycoside Hydrolases Goals Growth Human Hydrolysis In Vitro Life Link Malignant Neoplasms Mass Spectrum Analysis Methods Modeling Molecular Profiling Mutation Nutrient Pathway interactions Peptide Hydrolases Physiological Play Point Mutation Protein Glycosylation Proteins Proteolysis Regulation Research Role Signal Pathway Signal Transduction Site Stress Structure Substrate Specificity Therapeutic Tissue Sample arm attenuation cancer cell cancer type cell growth crosslink design disease diagnosis innovation insight interest novel novel therapeutic intervention peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase protein complex public health relevance response tumor progression

项目摘要

Abstract Human O-GlcNAcase (OGA) regulates a wide variety of essential biological processes by hydrolyzing O- GlcNAcylation from numerous proteins in response to nutrient and stress. Even though dysregulated OGA has been indicated in many diseases, little is known about how OGA's function is regulated. Dynamic function of OGA is mainly reflected by the changes of its substrate specificity, which is challenging to be characterized. One part of the challenge is the lack of information on OGA substrate recognition, as no apparent sequence motif can be defined in its substrate proteins. The other part of the challenge is the paucity of strategies to investigate OGA's substrate targeting and regulatory mechanism in cells. As a breakthrough in the field, we recently solved the first crystal structures of human OGA, revealing a unique structural feature that could contribute to substrate recognition. We propose to further characterize OGA's substrate specificity by solving new structures of OGA in complex with various substrates. We also propose to develop an innovative strategy to profile OGA's physiological substrates and binding partners in an effort to uncover the molecular signatures underlying the functional dysregulation of OGA in cancer development and programmed cell death. This study will provide unprecedented insights into the critical role of OGA in coupling O-GlcNAc biology to modulation of cell survival and death.

摘要人O-GlcNAc酶（OGA）通过水解O-葡萄糖来调节多种必需的生物过程。响应营养和胁迫的许多蛋白质的GlcNAc酰化。尽管OGA失调尽管OGA在许多疾病中被证明是有效的，但人们对OGA的功能是如何调节的却知之甚少。动态 OGA的功能主要体现在其底物特异性的变化上，这一点很难被表征了挑战的一部分是缺乏关于OGA底物识别的信息，因为没有表观序列基序可以在其底物蛋白中定义。挑战的另一部分是缺乏研究OGA在细胞中的底物靶向和调控机制的策略。作为在该领域的突破，我们最近解决了人类OGA的第一个晶体结构，揭示了一个独特的可能有助于底物识别结构特征。我们建议进一步表征OGA的通过解决OGA与各种底物的复合物的新结构来实现底物特异性。我们亦建议开发一种创新的策略来描述OGA的生理底物和结合伴侣，揭示OGA在癌症发展中功能失调的分子特征和程序性细胞死亡这项研究将提供前所未有的洞察OGA的关键作用，将O-GlcNAc生物学与细胞存活和死亡的调节偶联。