Most protein sequences contain one or several short aggregation prone regions (APR) that can nucleate protein
aggregation. Under normal conditions these APRs are protected from aggregation by protein interactions or because they
are buried in the hydrophobic core of native protein domains. However, mutation, physiological stress or age-related disregulation
of protein homeostasis increases the probability that aggregation-nucleating regions become solvent exposed.
Aggregation then results from the self-assembly of APRs into β-structured agglomerates that vary from small soluble oligomeric
assemblies to large insoluble inclusions containing thousands of molecules. The functional effects of APR-driven
aggregation are diverse and protein-specific leading to distinct disease phenotypes ranging from neurodegeneration to
cancer. On a cellular and physiological level both wild type loss-of-function as well as aggregation-dependent gain-offunction
effects have been shown to contribute to disease. Several molecular mechanism have been proposed to contribute
to gain-of-function activity of protein aggregates including cellular membrane disregulation, saturation of the protein
quality control machinery or the ability of aggregates to engage non-native interactions with proteins and nucleic acids.
These different mechanisms will all, to some extent, contribute to gain-of-function as in essence they all contribute to the
rewiring of the cellular interactome by aggregation-specific interactions, resulting for instance in the pronounced neurotoxicity
of TDP43 aggregates by the sequestration of RNA molecules or the promotion of cell proliferation by the entrapment
of homologous tumor suppressor proteins in p53 aggregates in cancer. In this review we discuss the mechanism of
APR driven aggregation and how APRs contribute to modifying the cellular interactome by recruiting both misfolded as
well as active proteins thereby inhibiting or activating specific cellular functions. Finally, we discuss the ubiquity of APRs
in protein sequences and how selective pressure shaped protein sequences to minimize APR aggregation.
Keywords: Protein aggregation, beta-structure, aggregation prone region (APR), gatekeeper, amyloid
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