Dr Daniel Ramirez - Washington University School of Medicine

Mass spectrometry profiling of biomolecular condensate proteins and their regulation by glucose metabolism and posttranslational OGlcNAc modification

Prion-like proteins are intrinsically disordered proteins (IDPs), which lack a stable 3D structure.  IDPs play a crucial role in the function of biomolecular condensates (BMCs), which are membraneless organelles essential for organization of cellular biochemistry.  BMCs are highly responsive to changes in the environment and nutrient availability.  The influence of glucose metabolism on BMCs and how it affects their function at a systems level is not well understood.  Disruption in the regulation of BMCs can lead to pathological protein aggregations linked to various chronic metabolic diseases. 

Our study aims to explore how the Hexosamine Biosynthetic Pathway (HBP), a part of glucose metabolism that produces the essential post-translational modification (PTM) O-linked-B-N-acetylglucosamine (O-GleNAc), affects BMC dynamics.  Our research is structured into three main goals: (1) profiling the solubility and RNA binding of BMC proteins under glucose and HBP flux using mass spectrometry (MS), (2) identifying crucial modification sites that influence BMC protein solubility and RNA interactions by examining their phosphorylation and O-GlcNAc modification patterns and (3) to determine the impact of glucose metabolism on the organization of nuclear speckles, which are a type of BMC important in RNA splicing and genome organization. 

By understanding how glucose metabolism and O-GleNAc modification influence BMC behaviour, we can gain valuable knowledge about the cellular processes that lead to protein aggregation diseases.  The outcomes of this research will offer novel therapeutic target, biomarkers, and treatments for various chronic diseases such as neurodegenerative disorders, diabetes, cancer and more where glucose metabolism is impaired.