Proteome-scale discovery of protein degradation and stabilization effectors

Juline Poirson, Hanna Cho, Akashdeep Dhillon, Shahan Haider, Ahmad Zoheyr Imrit, Mandy Hiu Yi Lam, Nader Alerasool, Jessica Lacoste, Lamisa Mizan, Cassandra Wong, Anne-Claude Gingras, Daniel Schramek and Mikko Taipale ()
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Juline Poirson: University of Toronto
Hanna Cho: University of Toronto
Akashdeep Dhillon: University of Toronto
Shahan Haider: University of Toronto
Ahmad Zoheyr Imrit: University of Toronto
Mandy Hiu Yi Lam: University of Toronto
Nader Alerasool: University of Toronto
Jessica Lacoste: University of Toronto
Lamisa Mizan: University of Toronto
Cassandra Wong: Mount Sinai Hospital
Anne-Claude Gingras: University of Toronto
Daniel Schramek: University of Toronto
Mikko Taipale: University of Toronto

Nature, 2024, vol. 628, issue 8009, 878-886

Abstract: Abstract Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable target space1,2. However, only a few of the hundreds of E3 ligases and deubiquitinases in the human proteome have been harnessed for this purpose, which substantially limits the potential of the approach. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation3–5, but there are currently no methods that can identify such effector proteins in a scalable and unbiased manner. Here we established a synthetic proteome-scale platform to functionally identify human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. Our results reveal that the human proteome contains a large cache of effectors of protein stability. The approach further enabled us to comprehensively compare the activities of human E3 ligases and deubiquitinases, identify and characterize non-canonical protein degraders and stabilizers and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3 ligases cereblon and VHL. Our study provides a functional catalogue of stability effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for the discovery of new proximity-dependent protein modulators.

Date: 2024
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DOI: 10.1038/s41586-024-07224-3

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