Protein-small molecule interaction map of the lysosome for novel ligand discovery
Untargeted co-fractionation mass spectrometry platform to map protein-metabolite interactions within the lysosome, enabling discovery of novel endogenous small-molecule ligands of lysosomal proteins with potential therapeutic applications.
Overview
This research program delivers an untargeted, proteome- and metabolome-wide approach to characterizing protein-metabolite interactions (PMIs) within the lysosome. By systematically mapping these interactions, the work aims to uncover endogenous small molecules that bind and modulate lysosomal proteins, opening new avenues for drug discovery and target identification. The lysosome is a critical organelle involved in cellular degradation, signaling, and metabolic regulation, making its protein-metabolite interactome a rich source of potential therapeutic targets.
Technical specifications
Key methodological features:
- Co-fractionation mass spectrometry adapted for untargeted, metabolome- and proteome-wide characterization of protein-metabolite interactions
- Use of lysosomes purified from mammalian cell lines (HeLa and HEK293)
- Two orthogonal chromatographic separations (size exclusion and ion exchange) to minimize false positives and ensure high-quality interaction networks
- Untargeted LC/MS-based metabolomics and proteomics of chromatographic fractions
- Co-elution analysis to delineate protein-metabolite interactors
- Bimolecular interaction assays and in silico modeling to validate selected protein-metabolite pairs
- Proven track record of identifying novel small-molecule regulators, including proteinogenic dipeptides and 2',3'-cyclic nucleotide monophosphates
Technology readiness level
The underlying co-fractionation mass spectrometry platform has been validated and applied to generate PMI networks demonstrating that many endogenous small molecules interact with and modulate protein function. The proposed research extends this validated methodology to the lysosomal compartment, with a planned two-year timeline. Selected protein-metabolite pairs will be validated through orthogonal experimental and computational approaches. The approach is at an advanced research stage with demonstrated feasibility, ready for collaborative expansion into organelle-specific interactome mapping.
About Boyce Thompson Institute
Boyce Thompson Institute (BTI) is an independent, nonprofit plant and molecular science research institute co-located on Cornell University’s Ithaca campus, offering a focused, collaborative environment. For corporate partners, controlled‑environment greenhouses and growth chambers, plus an on‑site phenotyping and imaging facility, enable rapid, reproducible trials and data‑rich evaluation using living plants. BTI’s Center for Translational Research and its Translational Program and Licensing run a startup incubator, manage IP and licensing, and connect companies with researchers for co‑development. Research is supported by competitive federal funding from agencies such as the National Science Foundation and the U.S. Department of Agriculture, alongside foundation support. A dedicated technology transfer office and Cornell integration provide clear pathways from discovery to commercialization.
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