Juan Bada - Single-molecule detection of protein PT modifications with a biological nanopore

Protein post-translational modifications (PTMs) play a crucial role in several biological processes, by profoundly modulating protein properties on both spatial and temporal scales. Protein PTMs have also emerged as reliable biomarkers for several diseases. However, only few techniques are available to accurately capture their complexity at a single molecule level and, therefore, to characterize their roles in health and disease. Nanopore sensing has emerged as a novel technique, which provides high sensitivity for the detection of low-abundance proteins, holding the potential to impact single-molecule proteomics and PTMs detection in particular. Here, we use a biological nanopore, the pore-forming toxin aerolysin, to detect and distinguish different alpha-synuclein-derived peptides bearing single or multiple PTMs, namely phosphorylation, nitration and oxidation occurring at different positions and in various combinations. The characteristic current signatures of the alpha-synuclein peptide and its PTM variants could be confidently identified using a deep learning model for signal processing. Our work highlights the unique advantage of using nanopore as a tool for simultaneous detection of multiple PTMs and paves the way for their use in biomarker discovery and diagnostics.
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