KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, 3000 Leuven, Belgium.
J Mol Biol. 2022 Oct 15;434(19):167790. doi: 10.1016/j.jmb.2022.167790. Epub 2022 Aug 12.
Sec secretory proteins are distinguished from cytoplasmic ones by N-terminal signal peptides with multiple roles during post-translational translocation. They contribute to preprotein targeting to the translocase by slowing down folding, binding receptors and triggering secretion. While signal peptides get cleaved after translocation, mature domains traffic further and/or fold into functional states. How signal peptides delay folding temporarily, to keep mature domains translocation-competent, remains unclear. We previously reported that the foldon landscape of the periplasmic prolyl-peptidyl isomerase is altered by its signal peptide and mature domain features. Here, we reveal that the dynamics of signal peptides and mature domains crosstalk. This involves the signal peptide's hydrophobic helical core, the short unstructured connector to the mature domain and the flexible rheostat at the mature domain N-terminus. Through this cis mechanism the signal peptide delays the formation of early initial foldons thus altering their hierarchy and delaying mature domain folding. We propose that sequence elements outside a protein's native core exploit their structural dynamics to influence the folding landscape.
Sec 分泌蛋白通过 N 端信号肽与细胞质蛋白区分开来，信号肽在翻译后易位过程中具有多种作用。它有助于通过减缓折叠、结合受体和触发分泌来将前体蛋白靶向易位体。虽然信号肽在易位后被切割，但成熟结构域会进一步运输和/或折叠成功能状态。信号肽如何暂时延迟折叠以保持成熟结构域易位能力仍不清楚。我们之前报道过，周质脯氨酰-肽基异构酶的折叠结构域景观会被其信号肽和成熟结构域特征改变。在这里，我们揭示了信号肽和成熟结构域之间的动态相互作用。这涉及信号肽的疏水性螺旋核心、与成熟结构域相连的短无规卷曲连接器以及成熟结构域 N 端的灵活变阻器。通过这种顺式机制，信号肽延迟了早期初始折叠结构域的形成，从而改变了它们的层次结构并延迟了成熟结构域的折叠。我们提出，蛋白质天然核心之外的序列元件利用其结构动力学来影响折叠景观。
