PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease

Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity – they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein–protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer’s disease. This review explores how PTMs within intrinsically disordered regions drive epichaperome formation, how these scaffolds selectively regulate disease-enabling functions, and why their disruption normalizes pathological networks. By highlighting PTMs as molecular encoders of supramolecular assemblies, we propose a shift from targeting proteins to targeting network architectures that sustain and perpetuate disease – a concept with broad implications for cell biology, disease propagation, and therapeutic design.