最近，美国加州理工大学的研究人员首次解开了一个长期存在的谜团，即泛素(ubiquitin)如何在泛素连接酶(ubiquitin ligases)的协助下，添加到控制细胞周期的特殊蛋白质上。这项研究发表在本周的Nature杂志上，或将有助于开发治疗癌症的新方法。
泛素是一种特殊的蛋白质，主要功能是标记需要被分解掉的蛋白质上，使其被水解，标记同一个靶蛋白往往需要4个或更多的泛素分子。在这项报告中，课题组对泛素添加到靶蛋白cyclin E和β-Catenin泛素化的过程进行研究，这两种靶蛋白能够控制细胞的周期。
泛素标记到被降解的蛋白质上，这一过程需要有三种不同的酶E1, E2和E3的参与。简而言之，即泛素活化酶E1激活泛素并将其转移到泛素交联酶E2上，随后泛素连接酶E3识别特定的需要被泛素化的靶蛋白，并将泛素从E2上转移到靶蛋白上。
尽管科学家已经了解了上述过程，但仍然存在一个问题：多个泛素链是以一种已装配好的形式被转移到靶蛋白上呢，还是泛素链一个一个的转移到靶蛋白上？
为了解决这个问题，Pierce通过一种生物学停格动画(biological stop-motion animation)进行演示，这种动画每秒钟可播放100幅图片，可以使研究人员观察泛素从E2上转移到cyclin E蛋白质底物上的每一步骤。
当然，对泛素化过程的探究并不止于此，研究人员将进一步对泛素连接酶E3快速转移泛素到靶蛋白上的分子机制进行研究。
生物谷推荐原始出处：
Nature 462, 615-619 (3 December 2009) | doi:10.1038/nature08595
Detection of sequential polyubiquitylation on a millisecond timescale
Nathan W. Pierce1, Gary Kleiger1, Shu-ou Shan2,3 " Raymond J. Deshaies1,3
1 Howard Hughes Medical Institute, Division of Biology, MC 156-29,
2 Division of Chemistry and Chemical Engineering, MC 147-75, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
3 These authors contributed equally to this work.
Correspondence to: Raymond J. Deshaies1,3 Correspondence and requests for materials should be addressed to R.J.D.
The pathway by which ubiquitin chains are generated on substrate through a cascade of enzymes consisting of an E1, E2 and E3 remains unclear. Multiple distinct models involving chain assembly on E2 or substrate have been proposed. However, the speed and complexity of the reaction have precluded direct experimental tests to distinguish between potential pathways. Here we introduce new theoretical and experimental methodologies to address both limitations. A quantitative framework based on product distribution predicts that the really interesting new gene (RING) E3 enzymes SCFCdc4 and SCF-TrCP work with the E2 Cdc34 to build polyubiquitin chains on substrates by sequential transfers of single ubiquitins. Measurements with millisecond time resolution directly demonstrate that substrate polyubiquitylation proceeds sequentially. Our results present an unprecedented glimpse into the mechanism of RING ubiquitin ligases and illuminate the quantitative parameters that underlie the rate and pattern of ubiquitin chain assembly.
