Dynamic periplasmic chaperone reservoir facilitates biogenesis of outer membrane proteins
Dynamic periplasmic chaperone reservoir facilitates biogenesis of outer membrane proteins
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DOI：
10.1073/pnas.1601002113
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发表时间：
2016-08-16
影响因子：
11.1
通讯作者：
Fleming, Karen G.
中科院分区：
文献类型：
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作者：
Costello, Shawn M.;Plummer, Ashlee M.;Fleming, Karen G.
外膜蛋白（OMP）的生物合成对细菌生理学至关重要，因为细胞被膜对细菌致病和抗生素耐药性至关重要。OMP的生物合成过程已在体内进行了研究，其每一个组成部分已在体外进行了研究。这项工作将体内和体外实验的参数和观察结果整合到一个整体计算模型中，称为“外膜蛋白生物发生模型”（OMPBioM）。我们使用OMPBioM以全球方式评估OMP生物发生。使用确定性和随机性的方法，我们能够模拟OMP在不同的遗传条件下的生物成因，其中每一个成功地复制实验观察。我们观察到，外膜蛋白在周质中具有延长的寿命，其中未折叠的外膜蛋白在折叠成其天然状态之前平均与伴侣蛋白进行数百次短暂的相互作用。我们发现，一些周质分子伴侣的功能主要是作为质量控制因素，这种功能补充折叠催化功能的其他分子伴侣。此外，发现生理折叠所需的β-桶组装机械复合体的有效率高于目前在体外观察到的有效率。总的来说，我们发现一个微调之间的平衡热力学和动力学参数最大化OMP折叠通量和最小化聚集和不必要的降解。总之，OMPBioM提供了OMP生物发生的全球视角，对这一重要途径产生了独特的见解。
Outer membrane protein (OMP) biogenesis is critical to bacterial physiology because the cellular envelope is vital to bacterial pathogenesis and antibiotic resistance. The process of OMP biogenesis has been studied in vivo, and each of its components has been studied in isolation in vitro. This work integrates parameters and observations from both in vivo and in vitro experiments into a holistic computational model termed "Outer Membrane Protein Biogenesis Model" (OMPBioM). We use OMPBioM to assess OMP biogenesis mathematically in a global manner. Using deterministic and stochastic methods, we are able to simulate OMP biogenesis under varying genetic conditions, each of which successfully replicates experimental observations. We observe that OMPs have a prolonged lifetime in the periplasm where an unfolded OMP makes, on average, hundreds of short-lived interactions with chaperones before folding into its native state. We find that some periplasmic chaperones function primarily as quality-control factors; this function complements the folding catalysis function of other chaperones. Additionally, the effective rate for the beta-barrel assembly machinery complex necessary for physiological folding was found to be higher than has currently been observed in vitro. Overall, we find a finely tuned balance between thermodynamic and kinetic parameters maximizes OMP folding flux and minimizes aggregation and unnecessary degradation. In sum, OMPBioM provides a global view of OMP biogenesis that yields unique insights into this essential pathway.