Spatiotemporally resolved mapping of extracellular proteomes via in vivo-compatible TyroID

Zijuan Zhang, Yankun Wang, Wenjie Lu, Xiaofei Wang, Hongyang Guo, Xuanzhen Pan, Zeyu Liu, Zhaofa Wu and Wei Qin ()
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Zijuan Zhang: Tsinghua University
Yankun Wang: Tsinghua University
Wenjie Lu: Tsinghua University
Xiaofei Wang: Chinese Academy of Sciences
Hongyang Guo: Tsinghua University
Xuanzhen Pan: Tsinghua University
Zeyu Liu: Tsinghua University
Zhaofa Wu: Chinese Academy of Sciences
Wei Qin: Tsinghua University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Extracellular proteins play pivotal roles in both intracellular signaling and intercellular communications in health and disease. While recent advancements in proximity labeling (PL) methods, such as peroxidase- and photocatalyst-based approaches, have facilitated the resolution of extracellular proteomes, their in vivo compatibility remains limited. Here, we report TyroID, an in vivo-compatible PL method for the unbiased mapping of extracellular proteins with high spatiotemporal resolution. TyroID employs plant- and bacteria-derived tyrosinases to produce reactive o-quinone intermediates, enabling the labeling of multiple residues on endogenous proteins with bioorthogonal handles, thereby allowing for their identification via chemical proteomics. We validate TyroID’s specificity by mapping extracellular proteomes and HER2-neighboring proteins using affibody-directed recombinant tyrosinases. Demonstrating its superiority over other PL methods, TyroID enables in vivo mapping of extracellular proteomes, including mapping HER2-proximal proteins in tumor xenografts, quantifying the turnover of plasma proteins and labeling hippocampal-specific proteomes in live mouse brains. TyroID emerges as a potent tool for investigating protein localization and molecular interactions within living organisms.

Date: 2025
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DOI: 10.1038/s41467-025-57767-w

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