Laman Trip Diederik S, van Oostrum Marc, Memon Danish, Frommelt Fabian, Baptista Delora, Panneerselvam Kalpana, Bradley Glyn, Licata Luana, Hermjakob Henning, Orchard Sandra, Trynka Gosia, McDonagh Ellen M, Fossati Andrea, Aebersold Ruedi, Gstaiger Matthias, Wollscheid Bernd, Beltrao Pedro
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Nat Biotechnol. 2025 May 2. doi: 10.1038/s41587-025-02659-z.
Despite progress in mapping protein-protein interactions, their tissue specificity is understudied. Here, given that protein coabundance is predictive of functional association, we compiled and analyzed protein abundance data of 7,811 proteomic samples from 11 human tissues to produce an atlas of tissue-specific protein associations. We find that this method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while cell-type-specific cellular structures, such as synaptic components, are found to represent a substantial driver of differences between tissues. Over 25% of associations are tissue specific, of which <7% are because of differences in gene expression. We validate protein associations for the brain through cofractionation experiments in synaptosomes, curation of brain-derived pulldown data and AlphaFold2 modeling. We also construct a network of brain interactions for schizophrenia-related genes, indicating that our approach can functionally prioritize candidate disease genes in loci linked to brain disorders.
尽管在绘制蛋白质-蛋白质相互作用图谱方面取得了进展，但其组织特异性仍未得到充分研究。在此，鉴于蛋白质共丰度可预测功能关联，我们汇编并分析了来自11种人体组织的7811个蛋白质组样本的蛋白质丰度数据，以生成组织特异性蛋白质关联图谱。我们发现这种方法概括了已知的蛋白质复合物和细胞的更大结构组织。稳定蛋白质复合物的相互作用在不同组织中得到很好的保留，而细胞类型特异性的细胞结构，如突触成分，被发现是组织间差异的一个重要驱动因素。超过25%的关联是组织特异性的，其中不到7%是由于基因表达的差异。我们通过在突触体中的共分级实验、对脑源性下拉数据的整理和AlphaFold2建模来验证大脑中的蛋白质关联。我们还构建了与精神分裂症相关基因的大脑相互作用网络，表明我们的方法可以在与脑部疾病相关的基因座中对候选疾病基因进行功能优先级排序。
