Spatially resolved profiling of protein conformation and interactions by biocompatible chemical cross-linking in living cells

Lili Zhao, Yuxin An, Nan Zhao, Hang Gao, Weijie Zhang, Zhou Gong, Xiaolong Liu, Baofeng Zhao, Zhen Liang, Chun Tang, Lihua Zhang (), Yukui Zhang and Qun Zhao ()
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Lili Zhao: Chinese Academy of Sciences
Yuxin An: Chinese Academy of Sciences
Nan Zhao: Chinese Academy of Sciences
Hang Gao: Chinese Academy of Sciences
Weijie Zhang: Chinese Academy of Sciences
Zhou Gong: Chinese Academy of Sciences
Xiaolong Liu: Chinese Academy of Sciences
Baofeng Zhao: Chinese Academy of Sciences
Zhen Liang: Chinese Academy of Sciences
Chun Tang: College of Chemistry and Molecular Engineering
Lihua Zhang: Chinese Academy of Sciences
Yukui Zhang: Chinese Academy of Sciences
Qun Zhao: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Unlocking the intricacies of protein structures and interactions within the dynamic landscape of subcellular organelles presents a significant challenge. To address this, we introduce SPACX, a method for spatially resolved protein complex profiling via biocompatible chemical cross(x)-linking with subcellular isolation, designed to monitor protein conformation, interactions, and translocation in living cells. By rapidly capturing protein complexes in their native physiological state and efficiently enriching cross-linked peptides, SPACX allows comprehensive analysis of the protein interactome within living cells. Leveraging structure refinement with cross-linking restraints, we identify subcellular-specific conformation heterogeneity of PTEN, revealing dynamic differences in its dual specificity domains between the nucleus and cytoplasm. Furthermore, by discerning conformational disparities, we identify 83 cytoplasm-exclusive and 109 nucleus-exclusive PTEN-interacting proteins, each associated with distinct biological functions. Upon induction of ubiquitin-proteasome system stress, we observe dynamic alterations in PTEN assembly and its interacting partners during translocation. These changes, including the identification of components and interaction sites, are characterized using the SPACX approach. Notably, SPACX enables identification of unique interacting proteins specific to PTEN isoforms, including PTEN and PTEN-Long, through the determination of sequence-specific cross-linking interfaces. These findings underscore the potential of SPACX to elucidate the functional diversity of proteins within distinct subcellular sociology.

Date: 2024
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DOI: 10.1038/s41467-024-52558-1

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