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

Abstract

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.

ALS/FTD: Evolution, Aging, and Cellular Metabolic Exhaustion

“…Indeed, it has been proposed that the protein deposits may in some cases be beneficial as they contribute to reducing the pool of intracellular pathogenic oligomers, regardless of the mechanism of their pathogenicity (molecular toxicity or turnover costs), and outside the cells, these deposits will be less likely to interfere with cellular functions, and also less costly as they would be less targeted (and less accessible) to the intracellular proteases ( 73 ). In studies of TAR DNA binding protein 43 (TDP-43), beneficial effects of protein aggregation has also been observed ( 66 , 68 ), suggesting that the toxicity occurs via a non-aggregated state, which we propose below is a state that is more easily subject to costly turnover.…”

“…Following DNA transcription, RNA molecules within a cell are bound by distinct sets of RNA-binding proteins that have the task of regulating the correct processing, transport, stability, and function/translation of proteins up to its final degradation. Proteins reach a native state but can change their folded structure if the environment changes (protein misfolding) leading to aggregates ( 66 , 67 ). Mutations can also induce conformational changes and aggregation ( 68 ).…”