Ubiquitin-like Protein Activation and Transfer

描述（由申请人提供）：泛素和泛素样蛋白的翻译后共价附着已成为一种主要的细胞调节机制，在控制细胞分裂、信号转导、胚胎发育、内吞运输和免疫应答中起重要作用。事实上，对连接泛素样修饰的途径的解除管制在许多疾病中起着作用，包括癌症、出生缺陷和帕金森病，并且一些病毒在感染期间劫持了这些途径。泛素样蛋白通过重塑其靶蛋白的表面、改变其靶蛋白的半衰期、酶活性、蛋白/蛋白相互作用、亚细胞定位或其他特性来发挥作用。哺乳动物中至少存在十种不同的泛素样修饰，不同的泛素样蛋白附着在靶标上会导致不同的生物学后果。因此，一个关键问题是给定的泛素样蛋白如何与正确的靶标协调。泛素样蛋白通过El、E2和E3酶的顺序作用，通过异肽链连接到它们的靶标上。泛素样蛋白通过其专用的El选择途径，它通过选择相应的E2来协调给定的泛素样蛋白与正确的途径。尽管泛素样蛋白控制了广泛的生物过程，但泛素样蛋白如何被E1选择并与其E2协调的分子细节仍然难以捉摸。缺乏el的结构数据仍然是我们对泛素样蛋白转移级联的理解的重大限制。建议的研究解决以下问题：el的结构是什么？结构的哪些特征是保守的，哪些是特定泛素样蛋白家族成员所特有的？泛素样蛋白是如何被el识别的？e2是如何被el识别的？e2是如何选择它们特定的泛素样蛋白的？回答这些问题对于所有涉及到泛素样蛋白家族调控的生物学领域都具有重要意义。

DESCRIPTION (provided by applicant): Post-translational covalent attachment of ubiquitin and ubiquitin-like proteins has emerged as a predominant cellular regulatory mechanism, with important roles in controlling cell division, signal transduction, embryonic development, endocytic trafficking and the immune response. Indeed, deregulation of the pathways for attaching ubiquitin-like modifications plays a role in a number of diseases, including cancer, birth defects and Parkinson's Disease, and several viruses hijack these pathways during infection. Ubiquitin-like proteins function by remodeling the surface of their target proteins, changing their target' s half-life, enzymatic activity, protein/protein interactions, sub cellular localization or other properties. At least ten different ubiquitin-like modifications exist in mammals, and attachment of different ubiquitin-like proteins to a target leads to different biological consequences. Thus, a key question is how a given ubiquitin-like protein is coordinated with the correct target. Ubiquitin-like proteins are attached via an isopeptide linkage to their targets by the sequential action of El, E2 and in many cases, E3 enzymes. Ubiquitin-like proteins are selected for the pathway by their dedicated El, which coordinates a given ubiquitin-like protein with the right pathway by also selecting the corresponding E2. Despite the wide range of biological processes controlled by ubiquitin-like proteins, the molecular details for how ubiquitin-like proteins are selected by an E1 and coordinated with their E2 remain elusive. Lack of structural data for Els remains a significant limitation in our understanding of ubiquitin-like protein transfer cascades. The proposed research addresses following questions: What are the structures of Els? Which features of the structure are conserved, and which are specific for a particular ubiquitin-like protein family member? How are ubiquitin-like proteins recognized by Els? How are E2s recognized by Els? How do E2s select their particular ubiquitin-like protein? Answering these questions will be of significance to all areas of biology involving regulation by a growing family of ubiquitin-like proteins.