The molecular basis for the induction of autophagy

描述(申请人提供)：细胞内的蛋白质周转受蛋白质合成和降解的调节。蛋白质降解的一个途径是自噬，它能够降解错误折叠的蛋白质和受损的细胞器。自噬的失调与多种癌症以及包括帕金森氏症和亨廷顿病在内的神经退行性疾病有关。由于自噬在正常细胞功能中的重要性及其在疾病状态下的失调，在过去的15年里，人们对自噬相关的研究产生了极大的兴趣。尽管人们对自噬的研究越来越感兴趣，但很少有与自噬相关的蛋白质结构被确定。因此，许多调控自噬的分子机制，包括ATG1/ULK1复合体的激活机制，仍有待阐明。ATG1/ULK1是调节自噬的最上游复合体，一旦激活就启动自噬。抑制Atg1/ULK1复合体的激活几乎完全抑制了自噬，表明Atg1/ULK1复合体是自噬的主要调节因子。我们的目标是了解调控ATG1/ULK1复合体启动自噬的分子机制，为诱导自噬提供分子基础。为此，我将对ATG1/ULK1复合体的非活性和活性形式进行结构和功能表征。这项工作将包括确定ATG1/ULK1复合体的结构，以及对复合体进行结构驱动的突变分析，以验证和进一步研究复合体激活的可能机制。此外，自噬已被证明是由用于减缓肿瘤进展的药物诱导的。因此，这项工作不仅将揭示诱导自噬的分子机制，而且可能会推动未来的药物设计朝着以ATg1/ULK1复合体为靶点诱导自噬的方向发展，并具有更高的特异性。 与公共卫生相关：自噬是一种帮助维持蛋白质内稳态的过程，在许多癌症中都是不受调控的，许多抑制癌症进展的药物是通过诱导自噬来发挥作用的。然而，引导自噬诱导的机制还不清楚。因此，了解这些机制将有助于深入了解这些抗癌药物的作用，允许设计更有效的抗癌药物，并另外导致新的药物靶点。

DESCRIPTION (provided by applicant): Protein turnover within a cell is regulated by protein synthesis and degradation. One pathway of protein degradation is autophagy, which is capable of degrading misfolded proteins and damaged organelles. A dysregulation of autophagy has been implicated in various cancers, and neurodegenerative diseases including Parkinson's and Huntington's disease. Due to the importance of autophagy in normal cellular function and its dysregulation in disease states there has been a significantly increased interest in autophagy related research within the last 15 years. Despite the increased interest in autophagy research, very few structures of autophagy related proteins have been determined. Therefore, many of the molecular mechanisms that regulate autophagy, including the mechanism of activation of the Atg1/ULK1 complex, remain to be elucidated. The Atg1/ULK1 is the most upstream complex that regulates autophagy and upon activation serves to initiate autophagy. Inhibition of Atg1/ULK1 complex activation results in the near complete inhibition of autophagy demonstrating that the Atg1/ULK1 complex is a master regulator of autophagy. Our goal is to understand the molecular mechanisms that regulate the initiation of autophagy by the Atg1/ULK1 complex, which will provide the molecular basis for the induction of autophagy. To this end, I will perform a structural and functional characterization of the inactive and active forms of the Atg1/ULK1 complex. This work will include structure determination of the Atg1/ULK1 complex as well as a structure driven mutational analysis of the complex to validate and further investigate possible mechanisms for complex activation. Additionally, autophagy has been shown to be induced by pharmaceutical drugs that are used to slow tumor progression. As a result, this work will not only reveal the molecular mechanisms for the induction of autophagy but may also drive future drug design towards targeting the Atg1/ULK1 complex to induce autophagy with higher specificity. PUBLIC HEALTH RELEVANCE: Autophagy, a process that helps maintain protein homeostasis, is dysregulated in numerous cancers and a number of pharmaceuticals that inhibit cancer progression act through the induction of autophagy. However, the mechanisms guiding the induction of autophagy are not understood. Therefore, gaining an understanding of these mechanisms will provide insight into the action of these cancer inhibiting pharmaceuticals, allow for the design of more potent cancer drugs, and additionally lead to novel drug targets.