Current topics in medicinal chemistry vol:12 issue:22 pages:2470-2478
Most proteins 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 -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-of-function effects have been shown to contribute to disease. Several molecular mechanism have been proposed to contribute to gain-of-function activity of protein aggregates includingcellular 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 ofthe 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 APRscontribute 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 minimizeAPR aggregation.