Abstract
Protein aggregation is associated with an increasing number of human disorders and premature aging. Moreover, it is a central concern in the manufacturing of recombinant proteins for biotechnological and therapeutic applications. Nevertheless, the unique architecture of protein aggregates is also exploited by nature for functional purposes, from bacteria to humans. The relevance of this process in health and disease has boosted the interest in understanding and controlling aggregation, with the concomitant development of a myriad of algorithms aimed to predict aggregation propensities. However, most of these programs are blind to the protein environment and, in particular, to the influence of the pH. Here, we developed an empirical equation to model the pH-dependent aggregation of intrinsically disordered proteins (IDPs) based on the assumption that both the global protein charge and lipophilicity depend on the solution pH. Upon its parametrization with a model IDP, this simple phenomenological approach showed unprecedented accuracy in predicting the dependence of the aggregation of both pathogenic and functional amyloidogenic IDPs on the pH. The algorithm might be useful for diverse applications, from large-scale analysis of IDPs aggregation properties to the design of novel reversible nanofibrillar materials.
Highlights
Protein aggregation is an inherent feature of polypeptides that lies behind the onset of a wide range of human pathologies, including Alzheimer’s and Parkinson’s diseases or type II diabetes [1,2].aggregation often occurs during protein recombinant production and downstream processing, becoming a major bottleneck for the marketing of protein-based drugs [3,4]
In order to develop a new theoretical model that can forecast the effect of pH on protein aggregation, we exploited our previous work on the N-terminus moiety of the measles virus phosphoprotein (PNT), an intrinsically disordered proteins (IDPs) model whose aggregation propensity was deeply analyzed in relation to pH and its net charge [33]
Staphilococcus aureus Bap is an extracellular protein able to self-assemble at acidic pH (≈ 4.5), In the last decades, the advances in the field of protein aggregation have resulted in the forming amyloid fibrils that scaffold the formation of a biofilm matrix [44]
Summary
Protein aggregation is an inherent feature of polypeptides that lies behind the onset of a wide range of human pathologies, including Alzheimer’s and Parkinson’s diseases or type II diabetes [1,2].aggregation often occurs during protein recombinant production and downstream processing, becoming a major bottleneck for the marketing of protein-based drugs [3,4]. Polypeptides are susceptible to suffering aggregation at every step during protein production, from recombinant expression and purification to formulation and storage [4]. This implies a constant monitorization and optimization of production conditions and processes, which is costly and time-consuming. Protein aggregation is not always deleterious, and organisms exploit the particular properties of amyloid protein assemblies for beneficial purposes [5,6,7]. This evidence has inspired the use of
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