Specificity of Ubiquitination

描述（由申请人提供）：泛素和泛素样蛋白（ublps）的翻译后修饰是一种主要的细胞调节机制。泛素化调节大量的生物过程，包括细胞分裂，免疫反应和胚胎发育。因此，泛素途径的缺陷与许多疾病相关，特别是癌症，以及与衰老相关的病症，如神经退行性病症和干旱性肌肉萎缩。除泛素外，在高等真核生物中还发现了10多种ublps。Ublps的结构和序列与泛素非常相似，但它们将目标指向不同的目标。因此，重要的是要了解定义泛素化过程的特异性的分子基础。我们的长期目标是了解泛素和ublps是如何定向到它们的特定靶点，以控制癌症和神经退行性疾病等疾病的过程。泛素通过涉及E1、E2和E3类中的一系列三种酶的级联反应连接到靶标。尽管这些酶的重要性，很少有人知道泛素是如何选择的泛素化酶。我们假设泛素化酶的特异性是由与泛素相互作用的正选择和针对错误的ublp的负选择的组合决定的。我们专注于E1，E2和E3酶参与细胞增殖和参与调节肿瘤抑制蛋白。因为这些酶对于细胞增殖是重要的，并且在导致癌症的途径中起作用，所以这些酶可以作为抗有丝分裂剂的良好靶点。最近批准的蛋白酶体抑制剂硼替佐米（VelcadeTM）治疗多发性骨髓瘤强调了靶向泛素和ublp途径中的酶的治疗潜力，并强调了了解这些酶的详细机制和特异性的重要性。我们计划一个多学科的方法，结合生化，酶学和结构分析的泛素化酶，酶的ublp共轭级联，突变体和复合物，以了解特异性的泛素化。

DESCRIPTION (provided by applicant): Post-translational modification by ubiquitin and ubiquitin-like proteins (ublps) is a predominant cellular regulatory mechanism. Ubiquitination regulates a vast array of biological processes, including cell division, the immune response, and embryonic development. As a result, defects in the ubiquitin pathway are associated with numerous diseases, particularly cancer, and disorders associated with aging, such as neurodegenerative disorders and arid muscle wasting. In addition to ubiquitin, over 10 ublps have been found in higher eukaryotes. Ublps have structures and sequences that closely resemble ubiquitin, but they direct their targets to distinct destinies. Therefore, it is important to understand the molecular bases that define the specificity of the ubiquitination process. Our long-term goal is to understand how ubiquitin and ublps are directed to their particular targets to control processes involved in diseases such as cancers and neurodegenerative disorders. Ubiquitin is ligated to targets by a cascade involving a series of three enzymes in classes known as E1, E2, and E3. Despite the importance of these enzymes, little is known how ubiquitin is selected by ubiquitinating enzymes. We hypothesize that the specificity of ubiquitinating enzymes is dictated by a combination of positive selection for interacting with ubiquitin, and negative selection against the wrong ublp. We are focusing on the E1, E2 and E3 enzymes involved in cell proliferation and involved in regulating tumor suppressor proteins. Because these enzymes are important for cell proliferation, and play roles in pathways that lead to cancers, these enzymes may serve as good targets for anti-mitogenic agents. The recent approval of the proteasome inhibitor Bortezomib (VelcadeTM) for treatment of multiple myeloma underscores the therapeutic potential for targeting enzymes in the ubiquitin, and ublp, pathways, and highlights the importance of understanding the detailed mechanisms and specificities of these enzymes. We plan a multidisciplinary approach that combines biochemical, enzymological and structural analysis of ubiquitinating enzymes, enzymes in ublp conjugation cascades, mutants and complexes, in order to understand the specificity of ubiquitination.