Structure-function analysis of DegP

广泛保守的丝氨酸蛋白酶HtrA家族参与胞外质蛋白质量控制。两个被充分研究的家族成员，大肠杆菌DegP和DegS是发挥保护和调节作用的未折叠蛋白反应的关键参与者。DegS感知蛋白质折叠缺陷并启动信号级联，控制包括degP在内的数十种应激启动子的活性。DegP在分子伴侣和蛋白酶功能之间切换，引导受损蛋白质进入修复或降解途径。最近的研究表明，DegP还可以在三种低聚体状态（六聚体、12聚体和24聚体）之间切换，并且不同的功能和结构特征可能相互关联。本研究计划旨在利用遗传、生化和结构方法详细描述决定低聚物状态开关及其生理后果的潜在分子机制。这些研究将有助于我们了解细菌包膜中应激感知、蛋白质修复和降解的一般原理。

The widely conserved HtrA family of serine proteases is involved in extracytoplasmic protein quality control. Two well studied family members, E. coli DegP and DegS are key players of the unfolded protein response performing protective and regulatory roles. DegS senses protein folding defects and initiates a signaling cascade that controls the activity of dozens of stress promoters including degP. DegP switches between molecular chaperone and protease functions channelling damaged proteins into either repair or degradation pathways. Recent work revealed that DegP switches also between three oligomeric states (hexamer, 12 and 24mer) and that different functional and architectural features might be interconnected. This research proposal aims at characterising in detail the underlying molecular mechanisms determining the switch of oligomeric state and their physiological consequences using genetic, biochemical and structural approaches. These studies will contribute to our understanding of the general principles of stress sensing, protein repair and degradation in the bacterial cell envelope.