Chemoproteomic profiling by a bioorthogonal probe reveals cell growth inhibition by histone H4 dopaminylation

Abstract

Dopaminylation, the covalent attachment of dopamine to the side chain of glutamine (Gln, Q) in proteins, has been identified as a class of posttranslational modification. Due to the limited number of substrates, the functions and underlying molecular mechanisms of dopaminylation are not fully characterized. Utilizing an alkyne-functionalized dopamine probe, we have developed a method to selectively enrich dopaminylated proteins in the whole-cell context. We identified 4,133 proteins potentially modified with dopamine and validated the modification of histone H4 glutamine 27 by dopamine (H4Q27dop). H4Q27dop mainly exerts transcriptional inhibition function in neuroblastoma cells, and can inhibit cell proliferation through downregulating cyclin D1 gene CCND1 transcription, a classical well-known proliferation booster. Our study provides a valuable resource of putative substrate proteins modified with dopamine and reveals a novel mechanism of dopamine regulating cell growth in a neuroblastoma cancer model.