KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, 3000 Leuven, Belgium.
Institute of Molecular Biology and Biotechnology, FoRTH, University of Crete, 70013 Heraklion, Crete, Greece.
Structure. 2018 May 1;26(5):695-707.e5. doi: 10.1016/j.str.2018.03.006. Epub 2018 Apr 5.
Secretory preproteins carry signal peptides fused amino-terminally to mature domains. They are post-translationally targeted to cross the plasma membrane in non-folded states with the help of translocases, and fold only at their final destinations. The mechanism of this process of postponed folding is unknown, but is generally attributed to signal peptides and chaperones. We herein demonstrate that, during targeting, most mature domains maintain loosely packed folding intermediates. These largely soluble states are signal peptide independent and essential for translocase recognition. These intermediates are promoted by mature domain features: residue composition, elevated disorder, and reduced hydrophobicity. Consequently, a mature domain folds slower than its cytoplasmic structural homolog. Some mature domains could not evolve stable, loose intermediates, and hence depend on signal peptides for slow folding to the detriment of solubility. These unique features of secretory proteins impact our understanding of protein trafficking, folding, and aggregation, and thus place them in a distinct class.
分泌前体蛋白携带信号肽，氨基末端融合到成熟结构域。在易位酶的帮助下，它们以未折叠状态被靶向穿过质膜，并且仅在最终目的地折叠。这个推迟折叠过程的机制尚不清楚，但通常归因于信号肽和伴侣蛋白。本文证明，在靶向过程中，大多数成熟结构域保持松散包装的折叠中间体。这些在很大程度上是可溶性的状态与信号肽无关，对于易位酶的识别是必不可少的。这些中间体由成熟结构域的特征促进：残基组成、升高的无序度和降低的疏水性。因此，成熟结构域的折叠速度比其细胞质结构同源物慢。一些成熟结构域不能形成稳定的、松散的中间体，因此依赖信号肽进行缓慢折叠，从而牺牲了可溶性。这些分泌蛋白的独特特征影响了我们对蛋白质运输、折叠和聚集的理解，因此将它们置于一个独特的类别中。
