ENZYMATIC MECHANISMS OF UBIQUITIN-LIKE PROTEIN CONJUGATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在高等真核生物(如泛素、NEDD8、SUMO、ISG15)中有十几种泛素样蛋白(UBL)，它们以不同的方式共价修饰无数底物以改变其靶标的功能。UBL通过平行的、但UB1特有的涉及E1、E2和E3酶的酶级联方式共价连接到靶标上。这些酶通常由多个蛋白质组合组成，超过700个人类蛋白质具有表明它们是E1、E2或E3酶的一部分的基序。尽管人们只知道这些蛋白质中的一小部分具有生理功能，但在过去的几年里，参与Ub1结合的蛋白质的缺陷与癌症、神经退行性疾病和病毒感染等疾病有关。我们正在确定选定的E1s、E2s、E3s、与UbL的络合物和与靶的络合物的结构，以便获得Ub1结合的催化机制的一般分子图。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are more than a dozen Ubiquitin-like proteins (Ubls) in higher eukaryotes (e.g. ubiquitin, NEDD8, SUMO, ISG15) that covalently modify myriad substrates to alter the functions of their targets in different ways. Ubls are covalently attached to targets by parallel, but Ubl-specific enzymatic cascades involving E1, E2, and E3 enzymes. These enzymes generally comprise multi-protein assemblies, and over 700 human proteins have motifs indicating that they are part of E1, E2, or E3 enzymes. Although the physiological functions are known for only a handful of these proteins, in the past few years defects in proteins involved in Ubl conjugation have been associated with diseases such as cancer, neurodegenerative disorders, and viral infections. We are determining the structures of selected E1s, E2s, E3s, complexes with Ubls, and complexes with targets in order to obtain a general molecular picture of catalytic mechanisms underlying Ubl conjugation.