Recognition of misfolded proteins by Lon, a AAA+ protease
Recognition of misfolded proteins by Lon, a AAA+ protease
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DOI：
10.1101/gad.1670908
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发表时间：
2008-08-15
影响因子：
10.5
通讯作者：
Sauer, Robert T.
中科院分区：
文献类型：
--
作者：
Gur, Eyal;Sauer, Robert T.
蛋白质在细胞中不断地展开，尤其是在压力条件下。变性多肽被Lon和相关的atp依赖的AAA（+）蛋白酶降解有助于防止有毒聚集体的形成和其他有害后果，但这些破坏性的酶机器如何区分受损和正确折叠的蛋白质尚不清楚。在这里，我们发现大肠杆菌可以识别富含芳香残基的特定序列，这些序列在未折叠的多肽中可以接近，但隐藏在大多数天然结构中。缺乏这种序列的变性多肽是很差的底物。Lon还可以展开和降解具有可识别标签的稳定折叠蛋白质。因此，蛋白质结构和适当靶向序列的定位允许Lon降解依赖或独立于蛋白质的折叠状态。我们的研究结果表明，Lon可以协同识别未折叠多肽中的多种信号，从而导致纳米摩尔结合，并形成一种区分不可逆损伤蛋白和瞬时未折叠结构元件的机制。
Proteins unfold constantly in cells, especially under stress conditions. Degradation of denatured polypeptides by Lon and related ATP-dependent AAA(+) proteases helps prevent toxic aggregates formation and other deleterious consequences, but how these destructive enzymatic machines distinguish between damaged and properly folded proteins is poorly understood. Here, we show that Escherichia coli Lon recognizes specific sequences-rich in aromatic residues-that are accessible in unfolded polypeptides but hidden in most native structures. Denatured polypeptides lacking such sequences are poor substrates. Lon also unfolds and degrades stably folded proteins with accessible recognition tags. Thus, protein architecture and the positioning of appropriate targeting sequences allow Lon degradation to be dependent or independent of the folding status of a protein. Our results suggest that Lon can recognize multiple signals in unfolded polypeptides synergistically, resulting in nanomolar binding and a mechanism for discriminating irreversibly damaged proteins from transiently unfolded elements of structure.