Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.
Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.
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DOI：
10.1021/acschemneuro.5b00134
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发表时间：
2015-08-19
影响因子：
5
通讯作者：
Ferreira PA
中科院分区：
文献类型：
--
作者：
Cho KI;Orry A;Park SE;Ferreira PA
亲环素是肽基顺反脯氨酰异构酶（PPI酶），其活性通常被环孢菌素A（CsA）（一种有效的免疫抑制剂）抑制。亲环蛋白也是分子伴侣。新出现的证据支持亲环蛋白呈现非重叠的PPI酶和伴侣活性。疾病相关底物、信号转导子和转录激活子3和5（STAT 3/STAT 5）、异质核核糖核蛋白A2 B1（hnRNPA 2B 1）和M-视蛋白的蛋白质稳态由Ranbp 2的亲环蛋白结构域（CY）的非重叠伴侣和PPI酶活性调节，Ranbp 2是控制选择性底物的核质穿梭和蛋白质稳态的多功能和模块化支架。虽然高度同源，CY和原型亲环素A（CyPA）目前不同的催化和CsA结合活性，由于这些亲环素之间独特的结构特征。我们探索了CY和CyPA之间的结构特性，以通过计算机筛选近900万个针对CY PPIase口袋的小分子（SM），并鉴定出对STAT 3、hnRNPA 2B 1和/或M-视蛋白蛋白抑制具有选择性生物活性的SM。我们发现了三种类型的SM，其增强了腺嘌呤刺激的STAT 3的转录活性而不改变潜在的和激活的STAT 3水平，下调hnRNPA 2B 1或M-视蛋白的蛋白质稳定，或这些的组合。此外，抑制hnRNPA 2B 1蛋白质稳态的SM也强烈地和选择性地抑制CY的PPIase活性。本研究揭示了Ranbp 2及其底物的CY多模式调节的化学探针，这种调节可能导致亲环素构象亚态相互转换引起的变构。结果还证明了CY在针对由Ranbp 2控制的疾病相关底物的药物发现中的可行性，并且它们为治疗干预开辟了新的机会。
Cyclophilins are peptidyl cis-trans prolyl isomerases (PPIases), whose activity is typically inhibited by cyclosporine A (CsA), a potent immunosuppressor. Cyclophilins are also chaperones. Emerging evidence supports that cyclophilins present non-overlapping PPIase and chaperone activities. The proteostasis of the disease-relevant substrates, signal transducer and activator of transcription 3 and 5 (STAT3/STAT5), heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and M-opsin, are regulated by non-overlapping chaperone and PPIase activities of the cyclophilin domain (CY) of Ranbp2, a multifunctional and modular scaffold which controls nucleocytoplasmic shuttling and proteostasis of selective substrates. Although highly homologous, CY and the archetypal cyclophilin A (CyPA) present distinct catalytic and CsA-binding activities owing to unique structural features between these cylophilins. We explored structural idiosyncrasies between CY and CyPA to screen in silico nearly 9 million small molecules (SM) against the CY PPIase pocket and identify SMs with selective bioactivity toward STAT3, hnRNPA2B1 and/or M-opsin proteostasis. We found three classes of SMs that enhance the cytokine-stimulated transcriptional activity of STAT3 without changing latent and activated STAT3 levels, down-regulate hnRNPA2B1 or M-opsin proteostasis, or a combination of these. Further, a SM which suppresses hnRNPA2B1 proteostasis also inhibits strongly and selectively the PPIase activity of CY. This study unravels chemical probes for multimodal regulation of CY of Ranbp2 and its substrates and this regulation likely results in the allosterism stemming from the interconversion of conformational substates of cyclophilins. The results also demonstrate the feasibility of CY in drug discovery against disease-relevant substrates controlled by Ranbp2 and they open new opportunities for therapeutic interventions.