LAFEM: A Scoring Model to Evaluate Functional Landscape of Lysine Acetylome

Protein lysine acetylation is a critical post-translational modification involved in a wide range of biological processes. To date, about 20,000 acetylation sites of Homo sapiens were identified through mass spectrometry–based proteomic technology, but more than 95% of them have unclear functional annotations because of the lack of existing prioritization strategy to assess the functional importance of the acetylation sites on large scale. Hence, we established a lysine acetylation functional evaluating model (LAFEM) by considering eight critical features surrounding lysine acetylation site to high-throughput estimate the functional importance of given acetylation sites. This was achieved by selecting one of the random forest models with the best performance in 10-fold cross-validation on undersampled training dataset. The global analysis demonstrated that the molecular environment of acetylation sites with high acetylation functional scores (AFSs) mainly had the features of larger solvent-accessible surface area, stronger hydrogen bonding–donating abilities, near motif and domain, higher homology, and disordered degree. Importantly, LAFEM performed well in validation dataset and acetylome, showing good accuracy to screen out fitness directly relevant acetylation sites and assisting to explain the core reason for the difference between biological models from the perspective of acetylome. We further used cellular experiments to confirm that, in nuclear casein kinase and cyclin-dependent kinase substrate 1, acetyl-K35 with higher AFS was more important than acetyl-K9 with lower AFS in the proliferation of A549 cells. LAFEM provides a prioritization strategy to large scale discover the fitness directly relevant acetylation sites, which constitutes an unprecedented resource for better understanding of functional acetylome. [Display omitted] •LAFEM is the first prioritization strategy to evaluate functional acetylome.•LAFEM enriches functional annotations of 15,410 acetylation sites.•Eight molecular features in LAFEM are related to the function of acetylation site.•Assessment of acetylation sites by LAFEM provide support for quantitative acetylomics. Not all acetylation sites contribute equally to fitness, which disturbs us to find out the core reason between different biological models. In fact, it is insufficient to evaluate functional acetylation sites only relying on quantification acetylome. Therefore, we developed LAFEM to comprehensively consider the mol