Mannosidases in Glycoprotein Biosynthesis & Catabolism

糖蛋白生物合成中的甘露糖苷酶

基本信息

  • 批准号:
    7417559
  • 负责人:
  • 金额:
    $ 30.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1992
  • 资助国家:
    美国
  • 起止时间:
    1992-05-01 至 2010-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to examine the structure, function, and mechanism of action for a set of enzymes required for the biosynthesis and catabolism of mammalian N-linked glycans. We have focused on the Class I (family 47) a-mannosidases in the N-glycan pathway since they act as committed steps in the synthesis of complex oligosaccharides by determining the extent of mannose trimming, and in some cases appear to control the rate of degradation of unfolded glycoproteins in the endoplasmic reticulum (ER). Three subfamilies of Class I mannosidases have emerged from our prior cloning studies. The ER mannosidase I subfamily cleaves a single residue from Man9GlcNAc2 to generate a specific Man8GlcNAc2 isomer. The Golgi mannosidase I subfamily cleaves Man9-8GlcNAc2 structures to Man5GlcNAc2. The third subfamily, termed EDEM for ER degradation enhancing a-mannosidase-like protein, do not appear to have an intrinsic hydrolase activity, but may have a lectin activity involved in glycoprotein degradation. Recently, both ER Man I and EDEM proteins have been implicated as key players in the targeting of unfolded glycoproteins for disposal in the ER. This application will examine the mechanism used by the Class 1 mannosidases to recognize unfolded glycoproteins for disposal with a goal of understanding how intervention in the process can lead to enhanced protein stability in human genetic diseases characterized by the rapid degradation of unfolded mutant glycoproteins. Four specific aims are addressed in this proposal. The first aim will test hypotheses for the novel hydrolase mechanism and specificity of binding by Class 1 mannosidases by a combination of mutagenesis, kinetic analysis, binding studies, and structural analysis to map the determinants of substrate recognition and catalysis among the hydrolase family members. The second aim will test hypotheses relating to the lectin binding specificity of EDEM subfamily members through in vitro binding studies using wild type and mutant forms of recombinant EDEM or EDEM sub-domains in combination with in vivo functional complementation in model ER-associated degradation (ERAD) systems. The third aim will test hypotheses relating to EDEM function by examining sequences necessary for localization and interactions with components of the ERAD machinery. The fourth aim will test hypotheses for the individual roles and mechanisms of regulation of members of the ERAD targeting machinery by a novel real-time RT-PCR strategy and by siRNA approaches.
描述(由申请人提供):本提案的长期目标是研究哺乳动物n链聚糖生物合成和分解代谢所需的一组酶的结构、功能和作用机制。我们关注的是n -聚糖途径中的I类(家族47)a-甘露糖苷酶,因为它们通过决定甘露糖修剪的程度,在合成复杂寡糖的过程中起着重要的作用,在某些情况下,它们似乎控制内质网(ER)中未折叠糖蛋白的降解速度。从我们之前的克隆研究中已经出现了三个I类甘露糖酶亚家族。ER甘露糖苷酶I亚家族从Man9GlcNAc2中切割一个残基,生成一个特定的Man8GlcNAc2异构体。高尔基甘露糖苷酶I亚家族将Man9-8GlcNAc2结构切割成Man5GlcNAc2。第三个亚家族,称为EDEM,即内质网降解增强a-甘露糖苷酶样蛋白,似乎没有内在的水解酶活性,但可能具有参与糖蛋白降解的凝集素活性。最近,内质网Man I和EDEM蛋白都被认为是内质网处理未折叠糖蛋白的关键参与者。本应用程序将检查第1类甘露糖苷酶用于识别未折叠糖蛋白并进行处理的机制,目的是了解在该过程中的干预如何导致以未折叠突变糖蛋白的快速降解为特征的人类遗传疾病中的蛋白质稳定性增强。

项目成果

期刊论文数量(33)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Isolation of a mouse Golgi mannosidase cDNA, a member of a gene family conserved from yeast to mammals.
  • DOI:
    10.1016/s0021-9258(17)36963-6
  • 发表时间:
    1994-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. Herscovics;J. Schneikert;A. Athanassiadis;K. Moremen
  • 通讯作者:
    A. Herscovics;J. Schneikert;A. Athanassiadis;K. Moremen
Isolation and expression of murine and rabbit cDNAs encoding an alpha 1,2-mannosidase involved in the processing of asparagine-linked oligosaccharides.
编码参与天冬酰胺连接寡糖加工的 α1,2-甘露糖苷酶的鼠和兔 cDNA 的分离和表达。
Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont.
  • DOI:
    10.1038/nchembio.278
  • 发表时间:
    2010-02
  • 期刊:
  • 影响因子:
    14.8
  • 作者:
    Zhu Y;Suits MD;Thompson AJ;Chavan S;Dinev Z;Dumon C;Smith N;Moremen KW;Xiang Y;Siriwardena A;Williams SJ;Gilbert HJ;Davies GJ
  • 通讯作者:
    Davies GJ
Vertebrate protein glycosylation: diversity, synthesis and function.
Cloning, expression, purification, and characterization of the murine lysosomal acid alpha-mannosidase.
鼠溶酶体酸性α-甘露糖苷酶的克隆、表达、纯化和表征。
  • DOI:
    10.1016/s0304-4165(97)00023-8
  • 发表时间:
    1997
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Merkle,RK;Zhang,Y;Ruest,PJ;Lal,A;Liao,YF;Moremen,KW
  • 通讯作者:
    Moremen,KW
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KELLEY W. MOREMEN其他文献

KELLEY W. MOREMEN的其他文献

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{{ truncateString('KELLEY W. MOREMEN', 18)}}的其他基金

Economical Modular One-Pot Multienzyme Synthesis of Human Milk Oligosaccharides
经济的模块化一锅多酶合成母乳低聚糖
  • 批准号:
    10575228
  • 财政年份:
    2023
  • 资助金额:
    $ 30.01万
  • 项目类别:
2013/2015 Glycobiology Gordon Research Conference & Gordon Research Seminar
2013/2015 糖生物学戈登研究会议
  • 批准号:
    8451685
  • 财政年份:
    2013
  • 资助金额:
    $ 30.01万
  • 项目类别:
QRT-PCR TRANSCRIPT ANALYSIS
QRT-PCR 转录本分析
  • 批准号:
    8363006
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
REGULATION OF ERAD- AND UPR-RELATED GENE EXPRESSION
ERA 和 UPR 相关基因表达的调控
  • 批准号:
    8363017
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
MICROARRAY VALIDATION OF DATA FROM WILD-TYPE AND MGAT5 KNOCK-OUT MOUSE TISSUES
野生型和 MGAT5 敲除小鼠组织数据的微阵列验证
  • 批准号:
    8363111
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
EXPRESSION/LABELING OF GLYCOPROTEINS FOR NMR-BASED STRUCTURE STUDIES
用于基于 NMR 的结构研究的糖蛋白表达/标记
  • 批准号:
    8361783
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
N-GLYCAN PROCESSING ENZYMES IN GLYCOPROTEIN MATURATION & QUALITY CONTROL
糖蛋白成熟中的 N-聚糖加工酶
  • 批准号:
    8361789
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
REGULATION OF TRANSCRIPTS RELATED TO RAT ASN-LINKED GLYCAN BIOSYNTHESIS
与大鼠 ASN 连接聚糖生物合成相关的转录调控
  • 批准号:
    8363015
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
ANALYSIS OF TRANSCRIPTS INVOLVED IN GLYCOCONJUGATE SYNTHESIS IN D MELANOGASTER
黑腹果蝇糖复合物合成中涉及的转录本分析
  • 批准号:
    8363041
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:
CHANGES IN GENE EXPRESSION IN NDST1 & NDST2 KNOCK-OUT MOUSE CELLS
NDST1 中基因表达的变化
  • 批准号:
    8363110
  • 财政年份:
    2011
  • 资助金额:
    $ 30.01万
  • 项目类别:

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