Deciphering intercellular signaling complexes by interaction-guided chemical proteomics

Jiangnan Zheng (), Zhendong Zheng, Changying Fu, Yicheng Weng, An He, Xueting Ye, Weina Gao and Ruijun Tian ()
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Jiangnan Zheng: Southern University of Science and Technology
Zhendong Zheng: Southern University of Science and Technology
Changying Fu: Southern University of Science and Technology
Yicheng Weng: Southern University of Science and Technology
An He: Southern University of Science and Technology
Xueting Ye: Southern University of Science and Technology
Weina Gao: Southern University of Science and Technology
Ruijun Tian: Southern University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Indirect cell–cell interactions mediated by secreted proteins and their plasma membrane receptors play essential roles for regulating intercellular signaling. However, systematic profiling of the interactions between living cell surface receptors and secretome from neighboring cells remains challenging. Here we develop a chemical proteomics approach, termed interaction-guided crosslinking (IGC), to identify ligand-receptor interactions in situ. By introducing glycan-based ligation and click chemistry, the IGC approach via glycan-to-glycan crosslinking successfully captures receptors from as few as 0.1 million living cells using only 10 ng of secreted ligand. The unparalleled sensitivity and selectivity allow systematic crosslinking and identification of ligand-receptor complexes formed between cell secretome and surfaceome in an unbiased and all-to-all manner, leading to the discovery of a ligand-receptor interaction between pancreatic cancer cell-secreted urokinase (PLAU) and neuropilin 1 (NRP1) on pancreatic cancer-associated fibroblasts. This approach is thus useful for systematic exploring new ligand-receptor pairs and discovering critical intercellular signaling events.

Date: 2023
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DOI: 10.1038/s41467-023-39881-9

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