Man does not live by intrinsically unstructured proteins alone: The role of structured regions in aggregation

Protein misfolding is a topic that is of primary interest both in biology and medicine because of its impact on fundamental processes and disease. In this review, we revisit the concept of protein misfolding and discuss how the field has evolved from the study of globular folded proteins to focusing mainly on intrinsically unstructured and often disordered regions. We argue that this shift of paradigm reflects the more recent realisation that misfolding may not only be an adverse event, as originally considered, but also may fulfil a basic biological need to compartmentalise the cell with transient reversible granules. We nevertheless provide examples in which structure is an important component of a much more complex aggregation behaviour that involves both structured and unstructured regions of a protein. We thus suggest that a more comprehensive evaluation of the mechanisms that lead to aggregation might be necessary.

Automated summary

Protein misfolding is a key topic in biology and medicine, influencing fundamental processes and diseases. This review discusses the evolution of the field, focusing on intrinsically unstructured regions and the potential biological significance of misfolding. The review highlights the importance of both structured and unstructured regions in protein aggregation behavior and suggests a more comprehensive evaluation of aggregation mechanisms.