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An artificial protein modulator reprogramming neuronal protein functions

Author

Listed:
  • Peihua Lin

    (Shanghai Jiao Tong University
    Zhejiang University)

  • Bo Zhang

    (Shanghai Jiao Tong University
    World Laureates Association (WLA) Laboratories)

  • 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
    Shanghai Jiao Tong University)

  • Chunhai Fan

    (Shanghai Jiao Tong University)

  • Fangyuan Li

    (Zhejiang University
    Shanghai Jiao Tong University School of Medicine
    Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province)

  • Daishun Ling

    (Shanghai Jiao Tong University
    World Laureates Association (WLA) Laboratories)

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.

Suggested Citation

  • Peihua Lin & Bo Zhang & Hongli Yang & Shengfei Yang & Pengpeng Xue & Ying Chen & Shiyi Yu & Jichao Zhang & Yixiao Zhang & Liwei Chen & Chunhai Fan & Fangyuan Li & Daishun Ling, 2024. "An artificial protein modulator reprogramming neuronal protein functions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46308-6
    DOI: 10.1038/s41467-024-46308-6
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    References listed on IDEAS

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    1. Xiangzhao Ai & Chris Jun Hui Ho & Junxin Aw & Amalina Binte Ebrahim Attia & Jing Mu & Yu Wang & Xiaoyong Wang & Yong Wang & Xiaogang Liu & Huabing Chen & Mingyuan Gao & Xiaoyuan Chen & Edwin K.L. Yeow, 2016. "In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    2. Sarah L. Lovelock & Rebecca Crawshaw & Sophie Basler & Colin Levy & David Baker & Donald Hilvert & Anthony P. Green, 2022. "The road to fully programmable protein catalysis," Nature, Nature, vol. 606(7912), pages 49-58, June.
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