Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome.
Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome.
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DOI：
10.1016/j.str.2018.03.006
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发表时间：
2018-05
期刊：
影响因子：
5.7
通讯作者：
Alexandra Tsirigotaki;K. Chatzi;M. Koukaki;Jozefien De Geyter;Athina G. Portaliou;Georgia Orfanoudaki;M. Sardis;M. B. Trelle;T. Jørgensen;S. Karamanou;A. Economou
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文献类型：
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作者：
Alexandra Tsirigotaki;K. Chatzi;M. Koukaki;Jozefien De Geyter;Athina G. Portaliou;Georgia Orfanoudaki;M. Sardis;M. B. Trelle;T. Jørgensen;S. Karamanou;A. Economou
分泌性前蛋白携带氨基末端与成熟结构域融合的信号肽。它们在翻译后的目标是在易位酶的帮助下以非折叠状态穿过质膜，并且仅在最终目的地折叠。这种延迟折叠过程的机制尚不清楚，但通常归因于信号肽和伴侣。我们在此证明，在靶向过程中，大多数成熟结构域维持松散包装的折叠中间体。这些很大程度上可溶的状态是独立于信号肽的并且对于转位酶识别是必需的。这些中间体受到成熟结构域特征的促进：残基组成、无序性增加和疏水性降低。因此，成熟结构域的折叠速度比其细胞质结构同源物慢。一些成熟结构域无法进化出稳定、松散的中间体，因此依赖于信号肽缓慢折叠，从而损害溶解度。分泌蛋白的这些独特特征影响了我们对蛋白质运输、折叠和聚集的理解，从而将它们归为一个独特的类别。
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.