Abstract
Escherichia coli is one of the most widely used hosts for the production of recombinant proteins. However, very often the target protein accumulates into insoluble aggregates in a misfolded and biologically inactive form. Bacterial inclusion bodies are major bottlenecks in protein production and are hampering the development of top priority research areas such structural genomics. Inclusion body formation was formerly considered to occur via non-specific association of hydrophobic surfaces in folding intermediates. Increasing evidence, however, indicates that protein aggregation in bacteria resembles to the well-studied process of amyloid fibril formation. Both processes appear to rely on the formation of specific, sequence-dependent, intermolecular interactions driving the formation of structured protein aggregates. This similarity in the mechanisms of aggregation will probably allow applying anti-aggregational strategies already tested in the amyloid context to the less explored area of protein aggregation inside bacteria. Specifically, new sequence-based approaches appear as promising tools to tune protein aggregation in biotechnological processes.
Highlights
In the last decade, protein aggregation has moved beyond being a mostly ignored area of protein chemistry to become a key topic both in medical and biotechnological sciences [1]
The formation of inclusion bodies (IBs) is the main bottleneck in protein production, narrowing the spectrum of relevant polypeptides obtained by recombinant techniques and hampering the development of top priority research areas such as the de novo design of novel proteins, the rational modification of natural proteins or structural and functional genomics
This review focuses mainly on the role played by intrinsic polypeptide properties in protein aggregation
Summary
Protein aggregation has moved beyond being a mostly ignored area of protein chemistry to become a key topic both in medical and biotechnological sciences [1]. A growing number of globular proteins not related to disease can be induced to generate similar fibrils in vitro, albeit in some cases only in non-native conditions, leading to the suggestion than the ability to form amyloids is intrinsic to many or all polypeptides when their normal folding pathways are compromised [47,48,49,50] This appears to be true for IBs as well since deposition in such structures has been reported in the recombinant expression of many, but not all, heterologous genes and in the high level expression of several endogenous genes [7,51,52]. The analysis, identification and disruption by mutation of sequential "hot spots" of aggregation has allowed the recovering from the E. coli supernatant of previously aggregated polypeptides [67,93,106]
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