Disease-linked mutations disrupt protein phase behavior

Many proteins contain intrinsically disordered regions, or IDRs, which are flexible sequences that do not participate in folding. IDRs mediate processes like phase separation, where condensed liquid droplets form within the cell. These protein-rich condensates include nucleoli and stress granules that are critical for intracellular functioning. But it remains unclear how mutated IDR sequences contribute to disease.

Veronica Verdile, Elisa De Paola and Maria Paola Paronetto, via Wikimedia Commons

Examples of biological condensates formed during phase separation.

Oliver Kipp, Karen Lewis, and colleagues at Texas State University and the University of Colorado Boulder published an article in the Journal of Biological Chemistry investigating how missense mutations in IDRs affect protein phase separation and disease risk. Researchers analyzed a database of disease-linked missense mutations and mapped these onto protein IDRs. They found that pathogenic missense mutations are enriched threefold in phase-separating IDRs, or PS IDRs, compared to other IDRs. Likewise, mutations of arginine and aromatic residues were disproportionately pathogenic, while serine, threonine and alanine substitutions tended to be benign. Applying these trends to mutations of uncertain clinical significance, researchers predict that half of those occurring in PS IDRs are pathogenic.

These findings connect single amino acid changes to altered protein condensation of PS IDRs, suggesting a mechanism for how missense mutations contribute to conditions such as Alzheimer’s disease and Parkinson’s disease, which are associated with abnormal protein aggregation. Future research aims to improve predictive models of the effects of mutations on PS IDRs by considering amino acid specificity and mapping subcellular locations of mutations.