The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

Abstract

Protein aggregation has been studied for at least 3 decades, and many of the principles that regulate this event are relatively well understood. Here, however, we present a different perspective to explain why proteins aggregate: we argue that aggregation may occur as a side-effect of the lack of one or more natural partners that, under physiologic conditions, would act as chaperones. This would explain why the same surfaces that have evolved for functional purposes are also those that favour aggregation. In the course of reviewing this field, we substantiate our hypothesis with three paradigmatic examples that argue for the generality of our proposal. An obvious corollary of this hypothesis is, of course, that targeting the physiological partners of a protein could be the most direct and specific approach to designing anti-aggregation molecules. Our analysis may thus inform a different strategy for combating diseases of protein aggregation and misfolding.

Aggregation is a Context-Dependent Constraint on Protein Evolution

“…With TDP-43, we observed the opposite trend. We have recently stressed the importance of protein interactions with chaperones to prevent aggregation (Masino et al, 2011;Louka et al, 2020;Temussi et al, 2021). Expression of a protein in a heterologous system will lead by definition to a situation in which natural interactions cannot occur (Gotor et al, 2020).…”

“…Indeed, the interfaces through which proteins interact are often highly aggregation prone, so that their engagement in interactions reduces propensity to selfassembly (Pechmann et al, 2009). This means that regions under the evolutionary pressure of protein function may be the same that lead to aberrant aggregation (Lee et al, 2010;Masino et al, 2011;Temussi et al, 2021). Any situation, such as mutations or anomalous expression, could result in disruption of these beneficial interactions with consequent aggregation and depletion of normal function.…”

Cryptic amyloidogenic regions in intrinsically disordered proteins: Function and disease association

“…Sequences are constrained by evolution to preserve proteins’ structure and function and prevent aberrant interactions. Despite this purifying selection, polypeptides retain a certain potential to self-assemble into amyloid fibrils that competes with folding and the attainment of native conformations [2] , [3] , [4] , [5] . Uncontrolled amyloid assembly has a detrimental impact on cell fitness, sequestering functional proteins into inactive complexes and/or generating cytotoxic species, a process connected with over 37 human pathologies including Alzheimer’s and Parkinson’s diseases [2] , [6] .…”

Amyloid fibrils act as a reservoir of soluble oligomers, the main culprits in protein deposition diseases

“…The aggregation of these proteins may occur as a side-effect of the lack of their natural partners, which act as chaperones in physiological conditions. [22] Increasing experimental evidence indicates that soluble αS oligomers are the most dangerous species, playing a crucial role in neurodegeneration. [6,10,20,[23][24][25] They have been reported to interact aberrantly with neuronal membranes, thus causing their disruption and, as a consequence, ionic dyshomeostasis in the cell.…”

“…The aggregation of these proteins may occur as a side‐effect of the lack of their natural partners, which act as chaperones in physiological conditions. [ 22 ]…”