Understanding and predicting protein misfolding and aggregation: Insights from proteomics

Abstract

Protein misfolding and aggregation are being found to be associated with an increasing number of human diseases and premature aging, either because they promote a loss of protein function or, more frequently, because the aggregated species gain a toxic activity. Despite potentially harmful, aggregation seems to be a generic property of polypeptide chains and aggregation-prone protein sequences seem to be ubiquitous, which, counterintuitively, suggests that they serve evolutionary conserved functions. The in vitro study of individual aggregation reactions of a large number of proteins has provided important insights on the structural and sequential determinants of this process. However, it is clear that understanding the role played by protein aggregation and its regulation in health and disease at the cellular, developmental, and evolutionary levels require more global approaches. The use of model organisms and their proteomic analysis hold the power to provide answers to such issues. In the present review, we address how, initially, computational large-scale analysis and, more recently, experimental proteomics are helping us to rationalize how, why and when proteins aggregate, as well as to decipher the strategies organisms have developed to control proteins aggregation propensities.

From de novo to ‘de nono’: The majority of novel protein coding genes identified with phylostratigraphy are old genes or recent duplicates

“…2017 ). Wilson et al calculated the ISD, a proxy for protein solubility ( Monsellier and Chiti 2007 ; Pallares and Ventura 2016 ), in all mouse proteins and found that: 1) de novo genes showed the highest level of ISD, which suggested they were preadapted to become novel genes because they encode proteins with low tendency toward aggregation; 2) ISD levels increased throughout mouse genes phylostrata.…”

From de novo to ‘de nono’: most novel protein coding genes identified with phylostratigraphy represent old genes or recent duplicates

“…It has been argued that de novo genes encoding for proteins that show low propensity to form aggregates, and thus are less prone to induce cytotoxicity, should be more likely to be fixed (Wilson et al 2017). Wilson and colleagues calculated the intrinsic structural disorder (ISD), a proxy for protein solubility (Monsellier and Chiti 2007;Pallares and Ventura 2016), in all mouse proteins and found that: 1) de novo genes showed the highest level of ISD, which suggested they were preadapted to become novel genes because they encode proteins with low tendency toward aggregation; 2) ISD levels increased throughout mouse genes phylostrata.…”

Genome evolution is driven by gene expression‐generated biophysical constraints through RNA‐directed genetic variation: A hypothesis

“…Aggregation can result from the increase of the local concentration of proteins and RNAs since their physicochemical properties make them prone to form aggregates. For example, protein aggregates can be seeded by increased local protein concentration, which might be critical at the protein production site and because many proteins contain aggregation‐prone intrinsically disordered regions . Protein aggregates can also be initiated by protein unfolding during translation, as peptides emerging from ribosomes can form “spurious” contacts with peptides from the same nascent polypeptide .…”

“…For example, protein aggregates can be seeded by increased local protein concentration, which might be critical at the protein production site and because many proteins contain aggregation‐prone intrinsically disordered regions . Protein aggregates can also be initiated by protein unfolding during translation, as peptides emerging from ribosomes can form “spurious” contacts with peptides from the same nascent polypeptide . Likewise, the physicochemical properties of RNAs, their ability to interact with each other through base pairing, and their ability to interact with RNA‐binding proteins that contain aggregation‐prone intrinsically disordered regions, make the RNAs prone to form aggregates .…”