Using Protein Engineering to Understand and Modulate Aggregation

Protein aggregation occurs through a variety of mechanisms, initiated by the unfolded, non-native, or even the native state itself. Understanding the molecular mechanisms of protein aggregation is challenging, given the array of competing interactions that control solubility, stability, cooperativity and aggregation propensity. An array of methods have been developed to interrogate protein aggregation, spanning computational algorithms able to identify aggregation-prone regions, to deep mutational scanning to define the entire mutational landscape of a protein’s sequence. Here, we review recent advances in this exciting and emerging field, focussing on protein engineering approaches that, together with improved computational methods, hold promise to predict and control protein aggregation linked to human disease, as well as facilitating the manufacture of protein-based therapeutics.