Structure-based machine-guided mapping of amyloid sequence space reveals uncharted sequence clusters with higher solubilities

Nikolaos Louros, Gabriele Orlando, Matthias Vleeschouwer, Frederic Rousseau () and Joost Schymkowitz ()
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Nikolaos Louros: VIB Center for Brain and Disease Research
Gabriele Orlando: VIB Center for Brain and Disease Research
Matthias Vleeschouwer: VIB Center for Brain and Disease Research
Frederic Rousseau: VIB Center for Brain and Disease Research
Joost Schymkowitz: VIB Center for Brain and Disease Research

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract The amyloid conformation can be adopted by a variety of sequences, but the precise boundaries of amyloid sequence space are still unclear. The currently charted amyloid sequence space is strongly biased towards hydrophobic, beta-sheet prone sequences that form the core of globular proteins and by Q/N/Y rich yeast prions. Here, we took advantage of the increasing amount of high-resolution structural information on amyloid cores currently available in the protein databank to implement a machine learning approach, named Cordax (https://cordax.switchlab.org), that explores amyloid sequence beyond its current boundaries. Clustering by t-Distributed Stochastic Neighbour Embedding (t-SNE) shows how our approach resulted in an expansion away from hydrophobic amyloid sequences towards clusters of lower aliphatic content and higher charge, or regions of helical and disordered propensities. These clusters uncouple amyloid propensity from solubility representing sequence flavours compatible with surface-exposed patches in globular proteins, functional amyloids or sequences associated to liquid-liquid phase transitions.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17207-3

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DOI: 10.1038/s41467-020-17207-3

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