ENZYMATIC MECHANISMS OF UBIQUITIN-LIKE PROTEIN CONJUGATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在高等真核生物中存在十几种泛素样蛋白（Ubls）（如泛素、NEDD 8、SUMO、ISG 15），它们通过共价修饰多种底物以不同方式改变其靶点的功能。 Ubls通过平行但Ubls特异性的涉及E1、E2和E3酶的酶级联与靶标共价连接。这些酶通常包含多蛋白质组装体，并且超过700种人类蛋白质具有表明它们是E1、E2或E3酶的一部分的基序。 虽然这些蛋白质中只有少数的生理功能是已知的，但在过去的几年中，参与Ubl缀合的蛋白质中的缺陷与疾病如癌症、神经退行性疾病和病毒感染有关。 我们正在确定选定的E1 s，E2 s，E3 s的结构，与Ubls的复合物，以及与目标的复合物，以获得Ubls共轭的催化机制的一般分子图像。

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.