Structural Biology &Bio-Informatics Division, Indian Institute of Chemical Biology (Council of Scientific &Industrial Research), 4, Raja S.C. Mullick Road, Kolkata, 700 032, India.
Krish Biotech Research Pvt. Ltd. T-1, QK-17 (Part) WBIIDC, Kalyani, Phase III, Nadia West Bengal 741 235, India.
Sci Rep. 2017 Feb 7;7:42017. doi: 10.1038/srep42017.
An understanding of the mechanisms underlying protein aggregation and cytotoxicity of the protein aggregates is crucial in the prevention of several diseases in humans. Ribosome, the cellular protein synthesis machine is capable of acting as a protein folding modulator. The peptidyltransferase center residing in the domain V of large ribosomal subunit 23S rRNA is the centre for the protein folding ability of the ribosome and is also the cellular target of several antiprion compounds. Our in vitro studies unexpectedly reveal that the partial unfolding or aggregation of lysozyme under reducing conditions in presence of the ribosome can induce aggregation of ribosomal components. Electrostatic interactions complemented by specific rRNA-protein interaction drive the ribosome-protein aggregation process. Under similar conditions the rRNA, especially the large subunit rRNA and in vitro transcribed RNA corresponding to domain V of 23S rRNA (bDV RNA) stimulates lysozyme aggregation leading to RNA-protein aggregate formation. Protein aggregation during the refolding of non-disulfide containing protein BCAII at high concentrations also induces ribosome aggregation. BCAII aggregation was also stimulated in presence of the large subunit rRNA. Our observations imply that the specific sequestration of the translation machine by aggregating proteins might contribute to their cytotoxicity.
了解蛋白质聚集和蛋白质聚集的细胞毒性的机制对于预防人类的几种疾病至关重要。核糖体是细胞内蛋白质合成的机器，能够作为蛋白质折叠调节剂。位于大亚基 23S rRNA 结构域 V 中的肽基转移酶中心是核糖体蛋白质折叠能力的中心，也是几种抗朊病毒化合物的细胞靶点。我们的体外研究出人意料地揭示，在存在核糖体的情况下，还原条件下溶菌酶的部分展开或聚集会诱导核糖体成分的聚集。静电相互作用辅以特定的 rRNA-蛋白质相互作用驱动核糖体-蛋白质聚集过程。在类似的条件下，rRNA，特别是大亚基 rRNA 和体外转录的与 23S rRNA 结构域 V 对应的 RNA (bDV RNA) 刺激溶菌酶聚集，导致 RNA-蛋白质聚集体的形成。在高浓度下非二硫键含有的蛋白质 BCAII 的复性过程中蛋白质的聚集也会诱导核糖体的聚集。在大亚基 rRNA 的存在下，BCAII 的聚集也得到了刺激。我们的观察结果表明，聚集蛋白对翻译机器的特异性隔离可能导致其细胞毒性。
