Protein codes promote selective subcellular compartmentalization

• 成果类型: Article
• 署名作者: Kilgore, Henry R.; Chinn, Itamar; Mikhael, Peter G.; Mitnikov, Ilan; Van Dongen, Catherine; Zylberberg, Guy; Afeyan, Lena; Banani, Salman F.; Wilson-Hawken, Susana; Lee, Tong Ihn; Barzilay, Regina; Young, Richard A.
• 署名单位: Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Massachusetts Institute of Technology (MIT)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9136
• DOI: 10.1126/science.adq2634
• 发表日期: 2025-03-07
• 页码: 1095-1101
• 关键词: joint-consensus-recommendation; liver cell fractions; controlled proteolysis; nascent polypeptides; sequence variants; CLASSIFICATION; association; prediction; GUIDELINES; STANDARDS

摘要

Cells have evolved mechanisms to distribute similar to 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.