A proteome-wide atlas of lysine-reactive chemistry

Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 u...

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Bibliographic Details
Published in:Nature chemistry 2021-11, Vol.13 (11), p.1081-1092
Main Authors: Abbasov, Mikail E, Kavanagh, Madeline E, Ichu, Taka-Aki, Lazear, Michael R, Tao, Yongfeng, Crowley, Vincent M, Am Ende, Christopher W, Hacker, Stephan M, Ho, Jordan, Dix, Melissa M, Suciu, Radu, Hayward, Matthew M, Kiessling, Laura L, Cravatt, Benjamin F
Format: Article
Language:English
Subjects:
Chemistry
Depth profiling
HEK293 Cells
Humans
Immune response
Immune system
Innate immunity
Ligands
Lysine
Lysine - chemistry
Proteins
Proteome - chemistry
Proteomes
Proteomics
Proteomics - methods
Structure-Activity Relationship
Structure-function relationships
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Summary:Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule-lysine interactions captured by the entire library. We used these latter 'scout' electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein-RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.
ISSN:1755-4330
1755-4349
DOI:10.1038/s41557-021-00765-4