Epichaperomes are supramolecular chaperone-centered scaffolds that form in disease-associated or intrinsically stressed states, such as cancer, Alzheimer's disease, Parkinson's disease, experimental traumatic brain injury, and pluripotent stem cell states. They are nucleated by HSP90 and HSC70, two chaperones known for their roles in protein folding and translocation. But in epichaperomes, these proteins do not behave the same. PTM codes, such as the phosphorylation of HSP90 at S226 and S255, drastically change their behavior.
Rather than folding proteins like canonical chaperones, epichaperomes act as scaffold hubs to reorganize protein interactions and organize molecular machines throughout the cell. Despite being able to profile epichaperome components with traditional AP-MS and profile native epichaperome assemblies with native PAGE immunoblotting, the protein composition, structure, and PTM codes of discrete epichaperome assembly states are poorly known. This work addresses that problem by isolating native epichaperome assemblies for native PAGE separation and MS proteomics, identifying shared and cell-specific co-chaperone modules and PTM codes throughout assemblies across divergent cell states. Future work involves applying this workflow to neurodegenerative disease by isolating epichaperomes from post-mortem human brain tissues, and performing native MS and in-gel crosslinking MS to predict the structure of epichaperome assembly states in ESCs, which are a useful epichaperome model. These investigations aim to decipher the structural logic of how epichaperomes form and operate in different cellular contexts, providing assembly-level context to guide the development and improvement of disease therapies.
ASMS 2026 was a great experience -- this was my 3rd year attending. I received a lot of great input from the native-MS and top-down MS field and had great conversations with my friends in the crosslinking MS space. One amazing work that I think is worth highlighting is from Lukas Eriksson at the University of Oxford, who developed an instrument to couple native-MS and cryo-EM! Also, the students from David Schriemer's group at University of Calgary show great work every year with inspiring contributions to spatial proteomics and crosslinking MS. I'm looking forward to next year!
If you're attending the Society for Neuroscience conference this November in Washington DC, I hope to see you there! Please reach out if you would like to connect.