Protein codes promote selective subcellular compartmentalization

Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must assemble. In this study, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. We developed a protein language model, ProtGPS, that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in the nucleolus. ProtGPS identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code but also a previously unrecognized code governing their distribution to diverse subcellular compartments.

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Publication Details

Journal
Science
Published
2025-02-06
DOI
https://doi.org/10.1126/science.adq2634
Citations
58
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
45.94

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article

Protein codes promote selective subcellular compartmentalization

Salman F. Banani, Regina Barzilay, Lena K. Afeyan, Catherine Van Dongen et al.
58 citations
Science
RNA and protein synthesis mechanisms
45.94
article

Protein codes promote selective subcellular compartmentalization

Salman F. Banani, Regina Barzilay, Lena K. Afeyan, Catherine Van Dongen, Henry R. Kilgore, Tong Ihn Lee, G Zylberberg, Peter G. Mikhael, Itamar Chinn, Susana Wilson-Hawken, Ilan Mitnikov, Richard A. Young
article en
58 citations

Abstract

Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must assemble. In this study, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. We developed a protein language model, ProtGPS, that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in the nucleolus. ProtGPS identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code but also a previously unrecognized code governing their distribution to diverse subcellular compartments.

ScienceVol. 387(6738)
Brigham and Women's Hospital (US), Harvard University (US), IIT@MIT (US), Abdul Latif Jameel Poverty Action Lab (US), Whitehead Institute for Biomedical Research (US), Massachusetts Institute of Technology (US)
National Science Foundation, Damon Runyon Cancer Research Foundation, Broad Institute, National Institutes of Health
Openalex Percentile: Top 0%
RNA and protein synthesis mechanisms
45.94
DOIOpen Access PDFOpenAlex
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