STRUCTURAL STUDIES OF CANCER-RELATED PROTEINS

癌症相关蛋白质的结构研究

• 批准号: 8363515
• 负责人: ZONGCHAO JIA
• 金额: $ 1.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363515
• 关键词: Binding; Calpain; Cysteine Protease; Data; Disease; EF Hand Motifs; Funding; Grant; Link; Malignant Neoplasms; National Center for Research Resources; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Signal Pathway; Source; Structure; Triad Acrylic Resin; United States National Institutes of Health; cost; flexibility; m-calpain

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The two Ca2+-dependent cysteine proteases, ¿- and ¿-calpain, are involved in various Ca2+-linked signal pathways, but differ markedly in their Ca2+ requirements for activation. Using diffraction data collected at CHESS, we have determined the structure of a ¿-like calpain, which has 85% ¿-calpain sequence (the first 48 and the last 62 residues of the large subunit are those from m-calpain) and a low Ca2+ requirement. This construct was used because ¿-calpain itself is too poorly expressed. The structure of ¿-like calpain is very similar in overall fold to that of m-calpain as expected, but differs significantly in two aspects. In comparison with m-calpain, the catalytic triad residues in ¿-like calpain, His and Cys, are much closer together in the absence of Ca2+; and significant portions of the Ca2+-binding EF-hand motifs are disordered and more flexible. These structural differences imply that Ca2+-free ¿-calpain may represent a partially activated structure, requiring lower Ca2+ concentration to trigger its activation

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 依赖于钙离子的两种半胱氨酸蛋白酶-和-钙蛋白参与了各种与钙相关的信号通路，但激活所需的钙离子却有很大的不同。利用在CHESS上收集的衍射数据，我们确定了一个类钙蛋白的结构，它含有85%的钙蛋白序列(大亚基的前48个和最后62个残基是来自m-钙蛋白的残基)，对钙的需求很低。之所以使用这种结构，是因为-calain本身表达得太差了。与预期的一样，类钙蛋白的结构在整体折叠上与m-钙蛋白非常相似，但在两个方面有明显的不同。与m-calain相比，类calain中的催化三联体残基His和Cys在无Ca~(2+)的情况下距离更近；与Ca~(2+)结合的EF-Hand基序中的很大一部分是无序的和更灵活的。这些结构上的差异表明，无钙钙蛋白可能代表了部分激活的结构，需要较低的钙离子浓度才能触发其激活