The folding and misfolding of multidomain proteins

Protein folding represents a vital process for any living organism. While significant insights have been gained from studying single-domain proteins, our current knowledge on the folding mechanisms of multidomain proteins remains relatively limited, primarily due to their inherent complexity. The principal aim of this review lies in summarizing the emerging view pertaining multi-domain folding, emphasizing their modular nature, which minimizes misfolding and facilitates evolutionary innovation. We discuss the energetic interplay between domains, highlighting particularly the cases where domain interactions lead to transient misfolded intermediates. These interactions can result in diverse effects, including cooperative folding and domain-specific perturbations, which are particularly relevant to the pathogenesis of neurodegenerative diseases like polyglutamine disorders. The review underscores the critical need to understand multidomain folding, to better comprehend and potentially mitigate the molecular underpinnings of protein misfolding diseases.