Peptidyl prolyl isomerases (PPIases) accelerate the rate limiting step of protein folding by catalyzing cis/trans isomerization of peptidyl prolyl bonds. The larger PPIases have been shown to be multi-domain proteins, with functions other than isomerization of the proline-containing peptide bond. Recently, a few smaller PPIases have also been described for their ability to stabilize folding intermediates. The yeast Fpr1 (FK506-sensitive proline rotamase) is a homologue of the mammalian prolyl isomerase FKBP12 (FK506-binding protein of 12 kDa). Its ability to stabilize stressed cellular proteins has not been reported yet. We had earlier reported upregulation of Fpr1 in yeast cells exposed to proteotoxic stress conditions. In this work, we show that yeast Fpr1 exhibits characteristics typical of a general chaperone of the proteostasis network. Aggregation of mutant huntingtin fragment was higher in Fpr1-deleted as compared to parental yeast cells. Overexpression of Fpr1 led to reduced protein aggregation by decreasing the amount of oligomers and diverting the aggregation pathway towards the formation of detergent-soluble species. This correlated well with higher survival of these cells. Purified and enzymatically active yeast Fpr1 was able to inhibit aggregation of mutant huntingtin fragment and luciferase in vitro in a concentration-dependent manner; suggesting a direct action for aggregation inhibitory action of Fpr1. Overexpression of yeast Fpr1 was able to protect E. coli cells against thermal shock. This work establishes the role of Fpr1 in the protein folding network and will be used for the identification of novel pharmacological leads in disease conditions.

肽基脯氨酰异构酶 (PPIases) 通过催化肽基脯氨酰键的顺/反异构化加速蛋白质折叠的限速步骤。较大的 PPIases 已被证明是多域蛋白质，具有除含脯氨酸肽键的异构化以外的功能。最近，一些较小的 PPIase 也被描述为具有稳定折叠中间体的能力。酵母 Fpr1（FK506 敏感脯氨酸旋转酶）是哺乳动物脯氨酰异构酶 FKBP12（12 kDa 的 FK506 结合蛋白）的同源物。尚未报道其稳定受压细胞蛋白的能力。我们早先报道了暴露于蛋白毒性应激条件的酵母细胞中 Fpr1 的上调。在这项工作中，我们表明酵母 Fpr1 表现出蛋白质稳态网络的一般伴侣的典型特征。与亲代酵母细胞相比，Fpr1缺失。Fpr1的过表达通过减少寡聚体的量和将聚集途径转向洗涤剂可溶性物质的形成而导致蛋白质聚集减少。这与这些细胞的较高存活率很好地相关。纯化的酶活性酵母 Fpr1 能够以浓度依赖性方式在体外抑制突变亨廷顿蛋白片段和荧光素酶的聚集；表明 Fpr1 的聚集抑制作用有直接作用。酵母 Fpr1 的过表达能够保护大肠杆菌细胞免受热冲击。这项工作确立了 Fpr1 在蛋白质折叠网络中的作用，并将用于鉴定疾病状况中的新药理先导。