Nature Communications (Mar 2024)

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,
  • Daishun Ling

DOI
https://doi.org/10.1038/s41467-024-46308-6
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 16

Abstract

Read online

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.