An artificial protein modulator reprogramming neuronal protein functions

Peihua Lin, Bo Zhang, Hongli Yang, Shengfei Yang, Pengpeng Xue, Ying Chen, Shiyi Yu, Jichao Zhang, Yixiao Zhang, Liwei Chen, Chunhai Fan, Fangyuan Li () and Daishun Ling ()
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Peihua Lin: Shanghai Jiao Tong University
Bo Zhang: Shanghai Jiao Tong University
Hongli Yang: Zhejiang University
Shengfei Yang: Zhejiang University
Pengpeng Xue: Zhejiang University
Ying Chen: Zhejiang University
Shiyi Yu: Zhejiang University
Jichao Zhang: Chinese Academy of Sciences
Yixiao Zhang: Shanghai Jiao Tong University
Liwei Chen: Shanghai Jiao Tong University
Chunhai Fan: Shanghai Jiao Tong University
Fangyuan Li: Zhejiang University
Daishun Ling: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Reversible protein phosphorylation, regulated by protein phosphatases, fine-tunes target protein function and plays a vital role in biological processes. Dysregulation of this process leads to aberrant post-translational modifications (PTMs) and contributes to disease development. Despite the widespread use of artificial catalysts as enzyme mimetics, their direct modulation of proteins remains largely unexplored. To address this gap and enable the reversal of aberrant PTMs for disease therapy, we present the development of artificial protein modulators (APROMs). Through atomic-level engineering of heterogeneous catalysts with asymmetric catalytic centers, these modulators bear structural similarities to protein phosphatases and exhibit remarkable ability to destabilize the bridging μ3-hydroxide. This activation of catalytic centers enables spontaneous hydrolysis of phospho-substrates, providing precise control over PTMs. Notably, APROMs, with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein by directly hydrolyzing hyperphosphorylated α-synuclein. Consequently, synaptic function is reinforced in Parkinson’s disease. Our findings offer a promising avenue for reprogramming protein function through de novo PTMs strategy.

Date: 2024
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DOI: 10.1038/s41467-024-46308-6

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