Site-resolved spatial and structural interactome of a human cell
- 1FMP Berlin
Abstract
The spatial and structural arrangement of proteins determine virtually every process in human cells. We combined gentle subcellular fractionation by differential ultracentrifugation with cross-linking mass spectrometry to systematically map this cellular proteome architecture with residue-level evidence, identifying 164,146 residue-to-residue links in HEK293 cells. These links capture spatial protein arrangement at a resolution sufficient to pinpoint protein localizations at sub-organelle level, determine protein orientations within cellular membranes, and identify inter-organelle contact sites. The residue-level information provides evidence for 18,074 direct protein-protein interactions (PPIs), which we integrate into AlphaFold-based pipelines to nominate PPI-mediating short linear motifs and generate assembly models of large protein complexes. Guided by these spatial and structural readouts, we discover new PPIs within the endomembrane system that regulate the compartmental localization of trafficking machinery. Leveraging a network topology-driven strategy, we augment our HEK293 dataset with PPI data from different cell lines and methods, expanding the spatial and structural interactome of human cells.
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BibTeX
@misc{zhang2026siteresolved,
title = {{Site-resolved spatial and structural interactome of a human cell}},
author = {Z. Zhang and N. Yokoyama and Y. Zhu and J. Ruta and J. Cheng and V. Natalia and T. Soykan and V. Haucke and F. Liu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.749775},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.749775v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Site-resolved spatial and structural interactome of a human cell
AU - Z. Zhang
AU - N. Yokoyama
AU - Y. Zhu
AU - J. Ruta
AU - J. Cheng
AU - V. Natalia
AU - T. Soykan
AU - V. Haucke
AU - F. Liu
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.749775
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.749775v1
AB - The spatial and structural arrangement of proteins determine virtually every process in human cells. We combined gentle subcellular fractionation by differential ultracentrifugation with cross-linking mass spectrometry to systematically map this cellular proteome architecture with residue-level evidence, identifying 164,146 residue-to-residue links in HEK293 cells. These links capture spatial protein arrangement at a resolution sufficient to pinpoint protein localizations at sub-organelle level, determine protein orientations within cellular membranes, and identify inter-organelle contact sites. The residue-level information provides evidence for 18,074 direct protein-protein interactions (PPIs), which we integrate into AlphaFold-based pipelines to nominate PPI-mediating short linear motifs and generate assembly models of large protein complexes. Guided by these spatial and structural readouts, we discover new PPIs within the endomembrane system that regulate the compartmental localization of trafficking machinery. Leveraging a network topology-driven strategy, we augment our HEK293 dataset with PPI data from different cell lines and methods, expanding the spatial and structural interactome of human cells.
ER -