Biomolecular condensates are microdroplets that form inside cells and serve to selectively concentrate proteins, RNAs and other molecules for a variety of physiological functions, but can contribute to cancer, neurodegenerative diseases and viral infections. The formation of these condensates is driven by weak, transient interactions between molecules. These weak associations can operate at the level of whole protein domains, elements of secondary structure or even moieties composed of just a few atoms. Different types of condensates do not generally combine to form larger microdroplets, suggesting that each uses a distinct class of attractive interactions. Here, we address whether polyproline II (PPII) helices mediate condensate formation. By combining with PPII‐binding elements such as GYF, WW, profilin, SH3 or OCRE domains, PPII helices help form lipid rafts, nuclear speckles, P‐body‐like neuronal granules, enhancer complexes and other condensates. The number of PPII helical tracts or tandem PPII‐binding domains can strongly influence condensate stability. Many PPII helices have a low content of proline residues, which hinders their identification. Recently, we characterized the NMR spectral properties of a Gly‐rich, Pro‐poor protein composed of six PPII helices. Based on those results, we predicted that many Gly‐rich segments may form PPII helices and interact with PPII‐binding domains. This prediction is being tested and could join the palette of verified interactions contributing to biomolecular condensate formation.
Do polyproline II helix associations modulate biomolecular condensates?