Structural Mechanisms of Hedgehog Autoprocessing in Physiology and Disease

Hedgehog（Hh）信号通路在发育和癌症中起着重要作用。Hh配体， 激活该途径的蛋白质来源于Hh前体蛋白的自动加工。Hh 自加工是在Hh信号通路的最开始，并可能在两者中起关键作用。 生理学和疾病。然而，Hh自动加工的基本机制及其在疾病中的作用是 不太了解。使用跨学科的方法，我们将定义Hh的催化机制 自动处理与原子分辨率和研究两个新的作用Hh自动处理在前列腺癌。我们 首先，我们将用溶液NMR确定Hh自处理的催化机理;然后，我们将研究一种新的 肿瘤发生机制涉及锌缺乏和Hh激活前列腺癌;最后，我们将 建立癌症药物的Hh自动加工作为前列腺癌耐药的新手段。

The Hedgehog (Hh) signaling pathway plays important roles in development and in cancer. The Hh ligand, which activates the pathway, is derived from the autoprocessing of the Hh precursor protein. Hh autoprocessing is at the very beginning of the Hh signaling pathway and likely plays crucial roles in both physiology and disease. However, the basic mechanisms of Hh autoprocessing and its role in diseases are poorly understood. Using an interdisciplinary approach, we will define the catalytic mechanism of Hh autoprocessing with atomic resolution and study two novel roles for Hh autoprocessing in prostate cancer. We will first define the catalytic mechanism of Hh autoprocessing with solution NMR; we will then study a new mechanism of tumorigenesis involving zinc deficiency and Hh activation in prostate cancer; lastly we will establish Hh autoprocessing of cancer drugs as a novel means of drug resistance in prostate cancer.