Probing the 14-3-3 Isoform-Specificity Profile of Protein–Protein Interactions Stabilized by Fusicoccin A,ACS Omega

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Probing the 14-3-3 Isoform-Specificity Profile of Protein–Protein Interactions Stabilized by Fusicoccin A
ACS Omega ( IF 3.7 ) Pub Date : 2020-09-24 , DOI: 10.1021/acsomega.0c01454
Ananya Sengupta ₁ , Josue Liriano ₁ , Ewa A. Bienkiewicz ₂ , Brian G. Miller ₁ , James H. Frederich ₁

Affiliation

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. Recently, FC has emerged as an important chemical probe of human 14-3-3 PPIs involved in cancer and neurobiology. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of 14-3-3 isoforms on FC activity remains underexplored. This is a relevant question for the continued development of FC variants because there are seven isoforms of 14-3-3 in humans. Despite their sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions in vivo. Herein, we interrogate the isoform-specificity profile of FC in vitro using recombinant 14-3-3 isoforms and a library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal recognition domains of client proteins that are characterized targets of FC in vivo. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3σ. Together, these data support the feasibility of developing FC variants with enhanced isoform selectivity.

中文翻译：

探索Fusicoccin A稳定的蛋白质-蛋白质相互作用的14-3-3同工型特异性谱

Fusicoccin A（FC）是一种真菌植物毒素，可稳定14-3-3衔接蛋白与其磷蛋白相互作用伴侣之间的蛋白-蛋白相互作用（PPI）。最近，FC已经成为人类14-3-3 PPI参与癌症和神经生物学的重要化学探针。这些先前的研究确定了FC诱导的14-3-3·客户磷蛋白复合物稳定的结构要求。然而，14-3-3亚型对FC活性的影响仍未开发。对于FC变体的持续发展，这是一个相关的问题，因为在人类中存在7种14-3-3同工型。尽管其序列和结构相似，但越来越多的实验证据支持体内14-3-3亚型的组织特异性表达和体内亚型特异性功能。在本文中，我们使用重组14-3-3同工型和荧光素标记的六磷酸肽库模拟体外FC的同工型特异性谱，该库模仿了表征FC体内靶标的客户蛋白质的C端识别域。我们的结果揭示了单个客户磷酸配体的适度同工型偏好，并证明了FC差异稳定了涉及14-3-3σ的PPI。总之，这些数据支持开发具有增强的同工型选择性的FC变体的可行性。

更新日期：2020-10-06

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