Structural and functional studies of alpha-N-terminal methylation

α-N-末端甲基化的结构和功能研究

• 批准号: RGPIN-2016-06300
• 负责人: Min, Jinrong
• 金额: $ 2.77万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709902
• 关键词: Structural; functional; studies; alpha; terminal

DNA, the recipe of human life, leads to the production of proteins in cells. These proteins then assemble together to form sub-microscopic machineries, necessary to create the miracle of life. Although they are numerically a pretty large number, the number of different genes encoded by our DNA is limited. This restricts, thus, the number of different proteins and their corresponding functions. As a result, evolution has designed a number of special genes in our DNA that leads to the production of special proteins capable of modifying all other proteins in particular ways, leading to an exponential increase in the diversity and dynamics of the entire population of human proteins contributing to the optimal function of human body. My research program at the University of Toronto is dedicated to investigate a unique class of these special protein modifying natural phenomena called -N-terminal methylation, which is literally the addition of a special chemical hat, methyl groups, to one specific end of proteins. Although our current knowledge on the biological functions of this special chemical hat is very little, recent research data suggest that this special chemical hat may play important diverse biological roles in higher living organisms. For example, research evidence suggest that the removal of this special chemical hat-encoding gene from the mouse DNA results in a high mortality rate shortly after birth as well as signs of premature aging and deficient DNA repair abilities, implying the potential involvement of this special chemical hat in human diseases particularly cancer. The key initiative from my research program will use a special technology called X-ray crystallography to visualize how this special chemical hat is added onto other cellular proteins by the special class of protein-modifying human proteins. This initiative will create a foundation on which this previously scientifically under-explored field of -N-terminal methylation, the ubiquitously present natural phenomenon of the addition of the special chemical hat onto human proteins, can expand. The discoveries spearheaded by my research program will not only further strengthen the global leadership position of Canada in biological sciences, but also contribute to the advent of therapeutic agents against human diseases associated with abnormal -N-terminal methylation in the near future, ultimately improving the health of Canadians and people around the world.

DNA，人类生命的配方，导致细胞中蛋白质的产生。然后，这些蛋白质组装在一起，形成亚微观机器，这是创造生命奇迹所必需的。尽管它们在数量上是一个相当大的数字，但我们DNA编码的不同基因的数量是有限的。因此，这限制了不同蛋白质的数量及其相应的功能。因此，进化在我们的DNA中设计了许多特殊的基因，导致能够以特定方式修改所有其他蛋白质的特殊蛋白质的产生，导致整个人类蛋白质种群的多样性和动态指数增加，有助于人体的最佳功能。我在多伦多大学的研究项目致力于研究一类独特的特殊蛋白质，这些特殊蛋白质可以改变自然现象，称为-N末端甲基化，它实际上是在蛋白质的一个特定末端添加一种特殊的化学帽子，甲基。尽管我们目前对这种特殊化学帽子的生物学功能知之甚少，但最近的研究数据表明，这种特殊化学帽子可能在高等生物中发挥着重要的多种生物学作用。例如，研究证据表明，从小鼠DNA中移除这种特殊的化学HAT编码基因会导致出生后不久的高死亡率，以及过早衰老和DNA修复能力不足的迹象，这意味着这种特殊的化学HAT可能与人类疾病，特别是癌症有关。我的研究计划中的关键举措将使用一种名为X射线结晶学的特殊技术来可视化这种特殊的化学HAT是如何通过特殊类别的蛋白质修饰人类蛋白质添加到其他细胞蛋白质上的。这一倡议将为这一之前科学上探索不足的-N-末端甲基化领域奠定基础，-N-末端甲基化是一种普遍存在的自然现象，即在人类蛋白质上添加特殊的化学HAT，可以在此基础上扩大。由我的研究计划带头的这些发现不仅将进一步巩固加拿大在生物科学方面的全球领先地位，而且还将有助于在不久的将来出现治疗与异常N-末端甲基化相关的人类疾病的药物，最终改善加拿大人和世界各地人民的健康。