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  3. Deciphering intercellular signaling complexes by interaction-guided chemical proteomics

Deciphering intercellular signaling complexes by interaction-guided chemical proteomics

  • Nat Commun. 2023 Jul 12;14(1):4138. doi: 10.1038/s41467-023-39881-9.
Jiangnan Zheng # 1,  Zhendong Zheng # 2 3,  Changying Fu # 2,  Yicheng Weng 2,  An He 2,  Xueting Ye 2,  Weina Gao 2,  Ruijun Tian 4 5
Affiliations

Affiliations

  • 1 Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, 518055, China. zhengjn@sustech.edu.cn.
  • 2 Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 3 School of Environment, Harbin Institute of Technology, Harbin, 150090, China.
  • 4 Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, 518055, China. tianrj@sustech.edu.cn.
  • 5 Research Center for Chemical Biology and Omics Analysis, School of Science, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen, 518055, China. tianrj@sustech.edu.cn.
  • # Contributed equally.
PMID: 37438365 DOI: 10.1038/s41467-023-39881-9
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.

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