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Spot in a drop: mutations in aberrant condensates

Nature Reviews Molecular Cell Biology volume 22, pages 162–163 (2021)Cite this article

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About 20 years ago we realized that most proteins can convert to amyloids from their native states. Amyloids are hallmarks of neurodegenerative diseases and form either via deposition of ordered aggregates or from highly dynamic condensates. While the first pathway is well characterized, the biophysical forces governing the conversion of liquid droplets to fibrils are less clear. In particular, our understanding of the mechanisms through which familial mutations modulate droplet properties leading to disease is incomplete.

Studies on cancer-associated mutations in the nuclear protein AKAP95 corroborate the notion that the biophysical properties of condensates that are important for their physiological functions result from generic interactions. Indeed, Li et al. demonstrated that the splicing activity of AKAP95 depends on the material properties of AKAP95-containing condensates; mutations that alter such properties alter the expression of various cancer-related genes. Replacing the disordered region in AKAP95 with unrelated sequences that drive liquid−liquid phase separation rescued AKAP95 splicing activity. These results show that dynamic interactions in liquid-like AKAP95 condensates, which can be achieved by chimeric sequences, ensure normal function.

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References

Original articles

  • Nikai, A. G. et al. RNA Interaction and aberrant phase separation induced by two distinct types of ALS/FTD-linked FUS mutations. Mol. Cell 77, 82–94 (2020)

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  • Li, W. et al. Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis. Nat. Cell Biol. 22, 960–972 (2020)

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  1. Department of Biomedical Sciences, University of Padova, Padova, Italy

    Monika Fuxreiter

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  1. Monika Fuxreiter
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Correspondence to Monika Fuxreiter.

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Fuxreiter, M. Spot in a drop: mutations in aberrant condensates. Nat Rev Mol Cell Biol 22, 162–163 (2021). https://doi.org/10.1038/s41580-021-00338-w

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