A proteome-wide dependency map of protein interaction motifs
Sara M Ambjørn1,2, Bob Meeusen1,2, Johanna Kliche1,2
1Center for Epigenetic Cell Memory, Danish Cancer Institute, Copenhagen, Denmark.
Nature Structural & Molecular Biology
|March 6, 2026
Summary
Researchers mapped essential short linear motifs (SLiMs) in the human proteome using base editing. This SLiM dependency map reveals numerous uncharacterized motifs crucial for cell proliferation and homeostasis.
Area of Science:
- Molecular Biology
- Proteomics
- Genomics
Background:
- Short linear motifs (SLiMs) are prevalent in human proteins but their role in cellular homeostasis is unclear.
- Systematic functional assessment of SLiMs is needed to understand their contribution to cellular processes.
Purpose of the Study:
- To systematically assess the function of reported and predicted Short Linear Motifs (SLiMs) using base editing.
- To create a comprehensive SLiM dependency map for the human proteome.
Main Methods:
- Applied base editing to mutate all reported and computationally predicted SLiMs.
- Screened 7,293 SLiM-containing regions with 80,473 mutations in HAP1 cells.
- Validated findings in RPE1 cells and identified binding partners for novel SLiMs.
Main Results:
- Generated a SLiM dependency map identifying 450 reported and 264 predicted SLiMs essential for cell proliferation.
- Demonstrated high reproducibility of mutational consequences across different cell lines (HAP1 and RPE1).
- Discovered novel SLiM classes and provided mechanistic insights into a disease-associated ANKRD17 mutation.
Conclusions:
- The study provides a proteome-wide resource on SLiM essentiality.
- Identified numerous uncharacterized essential SLiMs critical for cellular homeostasis and proliferation.
- Highlights the importance of SLiMs in understanding protein function and disease mechanisms.
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