Protein aggregate or agglomerate: similar punctate structure with distinct biological profiles

Under various physiological or pathological conditions, biomacromolecules may undergo assembly or misassembly to form puncta-shaped micro-structures in the cell. These assembled bodies contain a cluster of phase-separated proteins or nucleic acids. Therefore, it has long been recognized that disordered, misfolded or aggregated proteins entangled with their cellular interactome dominate in these “dot-like” compartments, exemplified by aggresome, stress granule, p-body, etc. Recently, the field has embarked on understanding their complex biological profiles, including the micro-organization (Ye et al, 2023), composition (Feng et al, 2023), and pathophysiology (Wang et al, 2021). In this work, (Levin et al, 2025) focused on the biological profiles of another type of protein assembly, namely “agglomerate” (Garcia-Seisdedos et al, 2019), induced by mutation of folded-state protein filamentation in yeast cells. In-depth proteomics profiling of cells containing protein agglomerates or aggregates revealed distinct quality control mechanisms in terms of their interactome and proteome-wide perturbations. This work, from a systems biology perspective, highlights the distinct biological profiles (interactome, cell fitness, proteome impact) determined by the protein foldedness inside these phenotypically similar cellular “dots”.